2,3-dihydro-1H-indene derivatives

ABSTRACT

Novel 2,3-dihydro-1H-indene derivatives and salts thereof represented by the general formula (1), ##STR1## [wherein R 1  and R 2  are each a hydrogen atom, a lower alkyl group, a phenyl group which may have halogen atoms and/or alkyl groups as the substituents on the phenyl ring; R 3  is a halgoen atom or a lower alkyl group; R 4  is a hydrogen atom, a halogen atom, a phenyl-lower alkyl group, a cycloalkyl-lower alkyl group or the like; R 5  is a hydroxyimino group, an alkylamino group or a group of the formula --NHR 8  (wherein R 8  is a hydrogen atom, a halogen-substituted lower alkanoyl group or the like); R 6  is a hydrogen atom or a phenyl group; and R 7  is a hydrogen atom or a lower alkyl group]. 
     The 2,3-dihydro-1H-indene derivatives and salt thereof are useful as improving agents for treating anoxemic and hypoxic symptoms and syndromes accompanied therewith, cerebral activators, amnesia curvative agents, presbyophrenia curvative agents, treating agents for breathing arrest and improving agents for hypoxia accompanied with potassium cyanide poisoning, as well as useful an anti-inflammatory agents and hypotensive agents.

This is a division of application Ser. No. 07/436,192, filed Nov. 14,1989, now U.S. Pat. No. 5,055,474 which is a divisional of Ser. No.247,401 filed Sep. 21, 1988, now U.S. Pat. No. 4,895,847 which is adivisional of Ser. No. 770,677, filed Aug. 29, 1985, now U.S. Pat. No.4,788,130.

FIELD OF THE INVENTION

The present invention relates to novel 2,3-dihydro-1H-indene derivativesand salts thereof having excellent activities for improving anoxemic andhypoxic symptoms and syndromes accompanied therewith, as well as havingexcellent anti-inflammatory, hypotensive, gastric juice secretioninhibitory actions, and further having excellent immunosupressiveactions.

Thus, the novel 2,3-dihydro-1H-indene derivatives and salts thereof areuseful as improving agents for treating anoxemic and hypoxic symptomsand syndromes accompanied therewith, cerebral activators, amnesiacurvative agents, presbyophrenia curvative agents, treating agents forbreathing arrest and improving agents for hypoxia accompanied withpotassium cyanide poisoning, as well as they are useful as prophylacticsfor arrhythmia and heart failure caused by hypoxia, as well as they areuseful as anti-inflammatory agents, hypotensive agents.

PRIOR ART AND PROBLEMS INVOLVED

Oxygen is one of the essential elements to the living body forsustaining the life through release of energies and metabolisms. In theliving body, oxygen is converted into so-called "active oxygenradicals", for example, oxygen anion radicals, peroxide ion, hydroxyradical, etc. in various biochemical reactions, such as energy releasingreactions, enzymatic reactions, and other reactions caused by exposuresin ultraviolet rays and various radiations.

The active oxygen radicals are indeed useful for the actions ofoxygenase and phagocytosis carried out by leucocytes. On the other hand,the active oxygen radicals promote peroxidation reaction of unsaturatedfatty acids, such as oleic acid, linoleic acid, linolenic acid andarachidonic acid, etc. These unsaturated fatty acid and existingabundantly in the living body, and are the main constituents of thebiomembranes. The peroxidation reaction of the unsaturated fatty acidsproduce peroxidized substances such as peroxidized lipids. Similar tothe active oxygen radicals, said peroxidized substances also producealkoxy radicals and hydroxy radicals which will attack the biomembranesand will result disorder of the biomembranes and deactivation of varioususeful enzymes working in the living body. Cf. "TAISHA" (Metabolisms),Vol. 15, No. 10, (1978), Special issue of active oxygen.

On the other hand, there are existing some other enzymes, such assuperoxide dismutase (hereinafter referred to as "SOD"), catalase,glutathion peroxidase, etc. in the living body. These enzymes preventthe deactivation of metabolism from the attack of the active oxygenradicals. Additionally, there are existing several vitamins, such astocopherols (vitamin E groups) having antioxidative activities in theliving body.

Generally, the normal homeostasis of the living body is sustained by theactions of these enzymes and vitamins having antioxidative activities.However, sometimes the phylaxis mechanisms of the living body beingsuitably maintained by the actions of these enzymes and vitamins may bedefected by certain reasons, and the formation of the active oxygenradicals in an amount exceeds to the ability of the phylaxis mechanismof the living body, as well as the formation and accumulation of theperoxidized substances are observed. In such cases that the phylaxismechanism of the living body is defected, then several severe disorderssuch as various diseases caused by the aggregation of the platelets,inflammations, disorder of the liver, arteriosclerosis, hemolysis,senescene or presbyopherenia, retinosis, disorder of the lungs,disorders of the heart and the lungs caused by the actions of certaindrugs, ischemic coronary heart disease and the like will be occurredaccompanaied with the progressive chain reactions of the peroxidation.

Hitherto, compounds having actions for scavenging the active oxygenradicals which are considered to be the main factors of theabove-mentioned various diseases, and for preventing or lowering theformation and accumulation of the peroxidized substances in the livingbody were known and called as antioxidants. A number of studies onprophylaxis and curative effects by using these anti-oxidants have beenreported in related literatures. As to enzymatic preparations containingSOD and other enzymes as mentioned previously are reported in"SUPEROXIDE TO IGAKU" (Superoxides and medicine) by Yoshihiko Ohyanagi,pp. 137-141, (1981), published from Kyoritsu Publishing Co., Ltd.Further, as to other antioxidants, such as butylhydroxytoluene (BHT),butylhydroxyanisol (BHA), tocopherol (vitamin E) and others are reportedin "IYAKU JOURNAL" (Pharmaceutical Journal), Vol. 19, No. 12, pp.2351-1359 (1983) by Makoto Mino, and Hidetaka Tanaka; Ibid., Vol. 19,No. 5, pp. 909-914 (1983), by Toshihiko Suematus.

Some indane compounds having chemical structural formula similar to thatof 2,3-dihydro-1H-indene derivative according to the present inventionare known in prior art literatures, for example, U.S. Pat. No. 2,916,490(M. Schenck, et al.), U.S. Pat. No. 3,637,740 (R. Sarges), JapanesePatent Pre-examination Application (Kokai) No. 245875 (1983) and J. Med.Chem., (1983), 26, pp. 580-585 (by A. A. Deana, et al.).

BRIEF SUMMARY OF THE INVENTION

The novel 2,3-dihydro-1H-indene derivatives and salts thereof of thepresent invention have excellent activities for scavenging the activeoxygen radicals and for preventing or lowering the formation of theperoxidized lipids in the living body. Therefore, the2,3-dihydro-1H-indene derivatives and salts thereof of the presentinvention are useful as preventive and curative agents for variousdiseases and disorders caused by excessive formation and accumulation ofthe active oxygen radicals, peroxidized substances such as peroxidizedlipids in the living body, and/or the defects of prophylaxis mechanismof the living body, for example anti-arteriosclerotic agents,anti-inflammatory agents, analgesics, autoimmune disease curvativeagents, platelets aggregation inhibitory agents, hypotensive agents,anti-hyperlipemic agents, retinosis of immature infant and cataractpreventive and curative agents. Furthermore, the 2,3-dihydro-1H- indenederivatives and salts thereof of the present invention are useful asimproving and curative agents for disturbances of consciousness causedby cerebrovascular disorder (for example, cerebral hemorrhage, cerebralinfarction, subarachnoidal hemorrhage and hypertensive encephalopathy),encephalitides, brain tumor, head injury, psychosis, metabolicdisturbance, drug intoxication and disturbances caused by physicalreasons, as well as are useful as treating and/or improving agents forsequelae caused by diseases, syndromes and symptoms, furthermore,aprosexia, hyperkinetic syndrome, speech disturbance and mentaldevelopment retardation.

The 2,3-dihydro-1H-indene derivatives and salts thereof are also usefulas antioxidants for oils and fats being contained in processed foods.

The 2,3-dihydro-1H-indene derivatives and salts thereof of the presentinvention are characterized as low toxicity with less side-effects.

An object of the present invention is to provide novel2,3-dihydro-1H-indene derivatives and salts thereof represented by thegeneral formula (1) mentioned below, having excellent pharmacologicalactivities as mentioned above.

Another object of the present invention is to provide processes forpreparing novel 2,3-dihydro-1H-indene derivatives and salts thereofrepresented by the general formula (1).

Further object of the present invention is to provide a pharmaceuticalcomposition containing 2,3-dihydro-1H-indene derivative or salt thereofrepresented by the general formula (1) as the active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

2,3-Dihydro-1H-indene derivatives and salts thereof of the presentinvention are novel compounds which have not been known in relatedliteratures up to the date, and are represented by the general formula(1) as follows: ##STR2## [wherein R¹ and R² are each a hydrogen atom, alower alkyl group, an unsubstituted phenyl group, a substituted phenylgroup having at least one substituent selected from the group consistingof a halogen atom and a lower alkyl group on the phenyl ring, anunsubstituted cycloalkyl group, a substituted cycloalkyl group having atleast one halogen atom as the substituent on the cycloalkyl ring, acyclo-alkyl-lower alkyl group, a hydroxy group, a phenyl-lower alkoxygroup, an unsubstituted phenyl-lower alkyl group or a substitutedphenyl-lower alkyl group having at least one substituent selected fromthe group consisting of a halogen atom, a lower alkylenedioxy group anda lower alkoxy group on the phenyl ring;

R³ is a halogen atom or a lower alkyl group;

R⁴ is a hydrogen atom, a halogen atom, a phenyl-lower alkyl group, acycloalkyl-lower alkyl group, a piperidinyl-lower alkanoylamino-loweralkyl group, a pyridinium-lower alkanoylamino-lower alkyl group or alower alkyl group;

R⁵ is a hydroxyimino group, an alkylamino group having 7 to 10 carbonatoms or a group of the formula --NHR⁸ ((wherein R⁸ is a hydrogen atom,a halogen-substituted lower alkanoyl group, a lower alkylamino-loweralkyl group, a phenyl-lower alkyl group or a group of the formula -A-B(wherein A is a lower alkylene group which may have at least one hydroxygroup as the substituent, a group of the formula --CO--(D)_(l) -- or--D--CO--, wherein D is a lower alkylene group, l is an integer of 0 or1; B is a 5- or 6-membered saturated or unsaturated heterocyclic groupwhich may have at least one substituent selected from the groupconsisting of a lower alkyl group which may have at least one hydroxygroup as the substituent, an oxo group, a carboxy group, a loweralkoxycarbonyl group, a pyridyl group, a phthalimido group, apyrrolidinylcarbonyl-lower alkyl group, an unsubstituted phenyl group, asubstituted phenyl group having 1 to 3 substituents selected from thegroup consisting of a halogen atom, a lower alkyl group which may haveat least one halogen atom as the substituent, a lower alkoxy group and anitro group on the phenyl ring, a phenyl-lower alkyl group and a benzoylgroup which may have at least one lower alkoxy group as the substituenton the phenyl ring)));

R⁶ is a hydrogen atom or a phenyl group;

R⁷ is a hydrogen atom or a lower alkyl group;

provided that, when R⁵ is a hydroxyimino group, R⁶ and R⁷ are each ahydrogen atom, or when R⁵ is a group of the formula --NHR⁸ (wherein R⁸is a hydrogen atom or a halogen-substitute lower alkanoyl group) andfurther R¹ and R² are each a hydrogen atom or a lower alkyl group, thenR⁴ should be neither a hydrogen atom, a lower alkyl group, a halogenatom, a nitro group, an amino group nor a lower alkanoylamino group.

In the present specification, the symbols of R¹, R², R³, R⁴, R⁵, R⁶ andR⁷ and more specifically exemplified as follows.

As to the lower alkyl group, a straight chain-or branched chain-alkylgroup having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, hexyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 2,3-dimethylpropyl, 1-methylpentyl,1,1-dimethylbutyl and 1-ethylbutyl groups can be exemplified.

As to the halogen atom, fluorine atom, chlorine atom, bromine atom andiodine atom can be exemplified.

As to the phenyl-lower alkyl group, a phenyl-alkyl group in which thealkyl moiety is a straight chain- or branched chain-alkyl group having 1to 6 carbon atoms, such as benzyl, 2-phenylethyl, 1-phenylethyl,3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl,5-phenylpentyl, 6-phenylhexyl and 2-methyl-3-phenylpropyl groups can beexemplified.

As to the cycloalkyl-lower alky group, a cycloalkylalkyl group having 3to 8 carbon atoms in which the alkyl moietyl is a straight chain- orbranched chain-alkyl group having 1 to 6 carbon atoms, such ascyclo-propylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl,2-cyclohexylethyl, 1-cyclohexylethyl, 1-cyclohexylpropyl,3-cyclopentylpropyl, 2-cyclopentylethyl, 4-cyclobutylbutyl,5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclopropylethyland 2-methyl-3-cyclopentylpropyl groups can be exemplified.

As to the halogen-substituted lower alkanoyl group, a straight chain- orbranched chain-alkanoyl group having 1 to 6 carbon atoms and having 1 to3 halogen atoms as the substituents, such as 2,2,2-trifluoroacetyl,2,2,2-trichloroacetyl, 2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl,2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl,3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloropropionyl,2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl,5-chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl and5,6-dibromohexanoyl groups can be exemplified.

As to the alkylene group which may have at least one hydroxy group asthe substituent, a straight chain- or branched chain-alkylene grouphaving 1 to 6 carbon atoms and which may have at least one hydroxy groupas the substituent, such as methylene, ethylene, trimethylene,2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,methylmethylene, ethylmethylene, tetramethylene, pentamethylene,hexamethylene, 1-hydroxymethylene, 1-hydroxyethylene,2-hydroxytrimethylene, 1-hydroxy-2--methyltrimethylene,1-hydroxy-2,2-dimethyltrimethylene, 1-methyl-2-hydroxytrimethylene,2-hydroxytetramethylene, 3-hydroxypentamethylene and4-hydroxyhexamethylene groups can be exemplified.

As to the lower alkylene group, a straight chain- or branchedchain-alkylene group having 1 to 6 carbon atoms, such as methylene,ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene and hexamethylene groups can be exemplified.

As to the 5- or 6-membered saturated or unsaturated heterocyclic ringgroup, such as piperazinyl, morpholino, thiomorpholino, piperidinyl,pyrrolidinyl, imidazolyl, pyridyl, pyrazolyl, isothiazol, isoxazolyl,pyrazinyl, pyrimidinyl, thienyl, furyl and pyranyl groups can beexemplified.

As to the lower alkoxycarbonyl group, a straight chain- or branchedchain-alkoxycarbonyl group having 1 to 6 carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isoproxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl groups can be exemplified.

As to the lower alkoxy group, a straight chain-or branched chain-alkoxygroup having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups can beexemplified.

As to the substituted phenyl group having 1 to 3 substituents selectedfrom the group consisting of a halogen atom, a lower alkyl group whichmay have halogen atoms as the substituents, a lower alkoxy group and anitro group on the phenyl ring, a substituted phenyl group having 1 to 3substituents selected from the group consisting of a halogen atom, astraight chain- or branched chain alkyl group having 1 to 6 carbon atomsand which may have 1 to 3 halogen atoms as the substituents, a straightchain- or branched chain alkoxy group having 1 to 6 carbon atoms and anitro group on the phenyl ring, such as 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl,4-iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl,3,4,5-trichlorophenyl, 2-trifluoromethylphenyl, 3-trichloromethylphenyl,4-chloromethylphenyl, 2-dibromomethylphenyl,3-(2,2,2-trifluoroethyl)-phenyl, 4-(1,2-dichloroethyl)phenyl,2-(5-chloropentyl)-phenyl, 3-(6-bromohexyl)phenyl,4-(5,6-dibromohexyl)phenyl, 2-iodomethylphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl,2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxypehnyl, 3-ethoxyphenyl,4-ethoxyphenyl 4-isopropoxyphenyl, 4-hexyloxyphenyl,3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4,5-trimethoxyphenyl,2,5-dimethoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,2,4-dinitrophenyl, 3-methyl-4-chlorophenyl, 2-chloro- 6-methylphenyl and2-methoxy-3-chlorophenyl groups can be exemplified.

As to the 5- or 6-membered saturated or unsaturated heterocyclic ringgroup which may have, as the substituents, selected from the groupconsisting of a lower alkyl group which may have hydroxy groups as thesubstituents, an oxo group, a carboxy group, a lower alkoxycarbonylgroup, a pyridyl group, a phthalimido group, apyrrolidinylcarbonyl-lower alkyl group, a phenyl group which may have 1to 3 substituents selected from the group consisting of a halogen atom,a lower alkyl group which may have halogen atoms as the substituents, alower alkoxy group and a nitro group on the phenyl ring, a phenyl-loweralkyl group and a benzoyl group which may have 1 to 3 lower alkoxygroups as the substituents on the phenyl ring, there can be exemplified5- or 6-membered saturated or unsaturated heterocyclic ring group whichmay have, as the substituents, selected from the group consisting of astraight chain- or branched chain-alkyl group having 1 to 6 carbon atomsand which may have hydroxy groups as the substituents, an oxo group, acarboxy group, a straight chain- or branched chain-alkoxycarbonyl grouphaving 1 to 6 carbon atoms, a pyridyl group, a phthalimido group, apyrrolidinylcarbonyl-C₁₋₆ -alkyl group, a phenyl group which may have 1to 3 substituents selected from the group consisting of a halogen atom,a straight chain- or branched chain-alkyl group having 1 to 6 carbonatoms and which may have 1 to 3 halogen atoms as the substituents, astraight chain-or branched chain-alkoxy group having 1 to 6 carbon atomsand nitro group, on the phenyl ring, a phenyl-C₁₋₆ -alkyl group, abenzoyl group which may have 1 to 3 C₁₋₆ -alkoxy groups as thesubstituents on the phenyl ring, such as 4-methyl-1-piperazinyl,4-butyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-hexyl-1-piperazinyl,3-ethyl-1-morpholino, 2-propyl-1-thiomorpholino, 4-methyl-1-piperidinyl,3-ethyl-1-pyrrolidinyl, 5-methylimidazolyl, 3-methylpyridyl,4-methylpyridyl, 3-methylpyrazolyl, 5-methylisothiazolyl,5-ethylisoxazolyl, 3-methyl-2-pyrazinyl, 4-pentyl-2-pyrimidinyl,5-propylthienyl, 5-methylfuryl, 4-hexylpyranyl,4-(hydroxymethyl)-1-piperazinyl, 4-(1-hydroxyethyl)-1-piperazinyl,4-(6-hydroxyphenyl)-1-piperazinyl, 2-(3-hydroxypropyl)-1-thiomorpholino,3-(2-hydroxyethyl)-1-morpholino, 4-hydroxymethyl)-1-piperidinyl,3-(2-hydroxyethyl)-1-pyrrolidinyl, 5-(hydroxymethyl)imidazolyl,3-(hydroxymethyl)pyridyl, 4-(1-hydroxyethyl)pyridyl,3-(hydroxymethyl)pyrazolyl, 5-(hydroxymethyl)isothiazolyl,5-(2-hydroxyethyl)isoxaxolyl, 3-hydroxymethyl-2-pyrazinyl,4-(5-hydroxypentyl)-2-pyrimidinyl, 5-(3-hydroxypropyl)-thienyl,5-hydroxymethylfuryl, 4-(6-hydroxyhexyl)pyranyl, 2-oxo-1-pyrrolidinyl,2-carboxy-1-pyrrolidinyl, 3-carboxy-1-pyrrolidinyl,4-carboxy-1-pyrrolidinyl, 2-methoxycarbonyl-1-pyrrolidinyl,2-ethoxycarbonyl-1-pyrrolidinyl, 3-propoxycarbonyl-1-pyrrolidinyl,4-butoxycarbonyl-1-pyrrolidinyl, 2-hexyloxycarbonyl-1-pyrrolidinyl,3-pentyloxycarbonyl-1-pyrrolidinyl, 4-(2-pyridyl)-1-piperazinyl,4-phenyl-1-piperazinyl, 4-(2-chlorophenyl)-1-piperazinyl,4-(3,5-dichlorophenyl)-1-piperazinyl,4-(2,3-dichlorophenyl)-1-piperazinyl, 4-(2-methoxyphenyl-1-piperazinyl,4-(4-nitrophenyl)-1-piperazinyl, 4-(2,3-dimethylphenyl)-1-piperazinyl,4-(2,4,5-trimethyl)-1-piperazinyl, 4-(3-methoxyphenyl)-1-piperazinyl,4-(3-methylphenyl)-1-piperazinyl, 4-(4-bromophenyl-1-piperazinyl,4-(3-fluorophenyl)-1-piperazinyl, 4-(2-iodophenyl)-1-piperazinyl,4-(2-butoxyphenyl)-1-piperazinyl, 4-(3-pentyloxyphenyl)-1-piperazinyl,4-(4-hexyloxyphenyl)-1-piperazinyl,4-(3,4,5-trimethoxyphenyl)-1-piperazinyl,4-(3-ethylphenyl)-1-piperazinyl, 4-(4-propylphenyl)-1-piperazinyl,4-(3-pentylphenyl)-1-piperazinyl, 4-(4-hexylphenyl)-1-piperazinyl,4-(3-butylphenyl)-1-piperazinyl, 4-benzyl-1-piperazinyl,4-(2-phenylethyl)-1-piperazinyl, 4-(3-phenylpropyl)-1-piperazinyl,4-(4-phenylbutyl)-1-piperazinyl,4-(1,1-dimethyl-2-phenylethyl)-1-piperazinyl,4-(5-phenylpentyl)-1-piperazinyl, 4-(6-phenylhexyl)-1-piperazinyl,4-(2-methyl-3-phenylpropyl)-1-piperazinyl, 4-benzoyl-1-piperazinyl,4-(2-methoxybenzoyl)-1-piperazinyl, 4-(3-methoxybenzoyl)-1-piperazinyl,4-(4-methoxybenzoyl)-1-piperazinyl, 4-(2-methoxybenzoyl)-1-piperazinyl,4-(4-isopropoxybenzoyl)-1-piperazinyl,4-(4-hexyloxybenzoyl)-1-piperazinyl,4-(3,4-dimethoxybenzoyl)-1-piperazinyl,4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl,4-(pyrrolidinylcarbonylmethyl)-1-piperazinyl,4-[2-(pyrrolidinylcarbonyl)-ethyl]-1-piperazinyl, 4-[1-(pyrrolidinylcarbonyl)ethyl]-1-piperazinyl,4-[4-(pyrrolidinylcarbonyl)butyl]-1-piperazinyl,4-[6(pyrrolidinylcarbonyl)hexyl]-1-piperazinyl,4-phthalimido-1-piperazinyl, 4-phthalimido-1-piperidinyl,4-(2-trifluoromethylphenyl)-piperazinyl,4-(3-trichloromethylphenyl)-1-piperazinyl,4-(4-chloromethylphenyl)-1-piperazinyl,4-[3-(2,2,2-trifluoroethyl)-phenyl]-1-piperazinyl,4-[4-(1,2-dichloroethyl)phenyl]-1-piperazinyl,4-[2-(5-chloropentyl)phenyl]-1-piperazinyl,4-[3-(6-bromohexyl)phenyl]-1-piperazinyl,4-[4-(5,6-dibromohexyl)phenyl]-1-piperazinyl and4-(2-iodomethylphenyl)-1-piperazinyl groups.

As to the piperidinyl-lower alkanoylamino-lower alkyl group, apiperidinylalkanoylaminoalkyl group in which the alkanoylamino moiety isa straight chain- or branched chain-alkanoylamino group having 2 to 6carbon atoms, and the alkyl moiety is a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms, such aspiperidinylacetylaminomethyl, (3-piperidinylpropionyl)aminomethyl,(4-piperidinylbutyryl)aminomethyl, (5-piperidinylpentanoyl)aminomethyl,(6-piperidinylhexanoyl)aminomethyl, 2-(piperidinylacetylamino)ethyl,1-[(3-piperidinylpropionyl)amino]ethyl,3-[(4-piperidinylbutyryl)amino]propyl,4-[(5-piperidinylpentanoyl)amino]-butyl,1,1-dimethyl-2-[(6-piperidinylhexanoyl)amino]ethyl,5-(piperidinylacetylamino)pentyl, 6-[(3-piperidinylpropionyl)amino]hexyland 2-methyl-3-(piperidinylacetylamino)propyl groups can be exemplified.

As to the alkylamino group having 7 to 10 carbon atoms, a straightchain- or branched chain-alkylamino group having 7 to 10 carbon atoms,such as heptylamino, octylamino, nonylamino and decylamino groups can beexemplified.

As to the pyridinium-lower alkanoylamino-lower alkyl group, apyridinium-alkanoylaminoalkyl group in which the alkanoylamino moiety isa straight chain- or branched chain alkanoylamino group having 2 to 6carbon atoms, and the alkyl moiety is a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms, such as pyridiniumacetylaminomethyl, (3-pyridinium propionyl)aminomethyl, (4-pyridiniumbutyryl)aminomethyl, (5-pyridinium pentanoyl)aminomethyl, (6-pyridiniumhexanoyl)aminomethyl, 2-(pyridinium acetylamino)ethyl, 1-[(3-pyridiniumpropionyl)amino]ethyl, 3-[(4-pyridinium butyryl)amino]propyl,4-[(5-pyridinium pentanoyl)amino]-butyl, 1,1-dimethyl-2-[(6-pyridiniumhexanoyl)amino]ethyl, 5-(pyridinium acetylamino)pentyl, 6-[(3-pyridiniumpropionyl)amino]hexyl and 2-methyl-3-(pyridinium acetylamino)propylgroups can be exemplified.

As to the substituted phenyl group having at least one substituentselected from the group consisting of a halogen atom and a lower alkylgroup on the phenyl ring, a substituted phenyl group having 1 to 3substituents selected from the group consisting of a halogen atom and astraight chain- or branched chain-alkyl group having 1 to 6 carbon atomson the phenyl ring, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl,3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl,3-methyl-4-chlorophenyl and 2-chloro-6-methylphenyl groups can beexemplified.

As to the unsubstituted cycloalkyl group, a cycloalkyl group having 3 to8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl groups can be exemplified.

As to the substituted cycloalkyl group having at least one halogen atomas the substituent on the cycloalkyl ring, a cycloalkyl group having 3to 8 carbon atoms and having 1 to 3 halogen atoms as the substituent onthe cycloalkyl ring, such as 1-chlorocyclopropyl, 1-bromocyclobutyl,2-chlorocyclobutyl, 1-chlorocyclopentyl, 2-bromocyclopentyl,1-chlorocyclohexyl, 2-bromocyclohexyl, 3-fluorocyclohexyl,1-chlorocycloheptyl, 2-bromocycloheptyl, 3-fluorocycloheptyl,4-iodocycloheptyl, 1-chlorocyclooctyl, 2-bromocyclooctyl,3-fluorocyclooctyl, 4-iodocyclooctyl, 1,2-dichlorocyclopentyl,2,3-dibromocyclohexyl, 2,4-dichlorocycloheptyl, 3,4-dibromocyclooctyl,2,3,4-trichlorocyclohexyl, and 2-bromo-4,4-dichlorocyclohexyl groups canbe exemplified.

As to the phenyl-lower alkoxy group, a phenylalkoxy group in which thealkoxy moiety is a straight chain- or branched chain-alkoxy group having1 to 6 carbon atoms, such as benzyloxy, 2-phenylethoxy, 1-phenylethoxy,3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy,5-phenylpentyloxy, 6-phenylhexyloxy and 2-methyl-3-phenylpropoxy groupscan be exemplified.

As to the substituted phenyl-lower alkyl group having at least onesubstituent selected from the group consisting of a halogen atom, alower alkoxy group and a lower alkylenedioxy group on the phenyl ring, asubstituted phenylalkyl group in which the alkyl moiety is a straightchain- or branched chain-alkyl group having 1 to 6 carbon atoms, andhaving 1 to 3 substituents selected from the group consisting of ahalogen atom and a straight chain-or branched chain-alkoxy group having1 to 6 carbon atoms on the phenyl ring, and having one straight chain-or branched chain-alkylenedioxy group having 1 to 4 carbon atoms on thephenyl ring, there can be exemplified, such as (2-chlorophenyl)methyl,2-(3-chlorophenyl)ethyl, 1-(4-chlorophenyl)ethyl,3-(2-fluorophenyl)propyl, 4-(3-bromophenyl)butyl,1,1-dimethyl-2-(4-iodophenyl)ethyl, 5-(3,5-dichlorophenyl)pentyl,6-(3,4-difluorophenyl)hexyl, 2-methyl-3-(3,4,5-trichlorophenyl)propyl,(2,6-dibromophenyl)methyl, (2-methoxyphenyl)methyl,2-(3-ethoxyphenyl)-ethyl, 1-(4-isopropoxyphenyl)ethyl,3-(4-hexyloxyphenyl)-propyl, 4-(3,4-dimethoxyphenyl)butyl, 1,1-dimethyl-2-(2,5-dimethoxyphenyl)ethyl, 5-(3,4,5-trimethoxyphenyl)pentyl,6-(3-pentyloxyphenyl)hexyl, 2-methyl-3-(2-n-butyloxyphenyl)-propyl,3,4-methylenedioxybenzyl, 2-(2,4-methylenedioxyphenyl)ethyl,1-(3,4-ethylenedioxyphenyl)ethyl, 3-(2,3-trimethylenedioxyphenyl)propyl,4-(3,4-tetramethylenedioxyphenyl)butyl,1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethyl,5-(2,3-methylenedioxyphenyl)pentyl and 6-(3,4-ethylenedioxyphenyl)hexylgroups.

As to the lower alkylamino-lower alkyl group, an alkylaminoalkyl groupin which the alkyl moiety is a straight chain- or branched chain-alkylgroup having 1 to 6 carbon atoms, and the alkylamino moiety is an aminogroup having 1 to 2 straight chain- or branched chain-alkyl groupshaving 1 to 6 carbon atoms as the substituents, such asmethylaminomethyl, 2-(ethylamino)-ethyl, 1-(propylamino)ethyl,3-(n-butylamino)propyl, 4-(pentylamino)butyl, 5-(hexylamino)pentyl,6-(dimethylamino)hexyl, 2-methyl-3-(diethylamino)propyl,1,1-dimethyl-2-(diisopropylamino)ethyl, 3-(dihexylamino)propyl,4-(methylethylamino)butyl, 5-(methylpentylamino)pentyl,6-(ethylpropylamino)hexyl, 2-methyl-3-(methylhexylamino)-propyl and1,1-dimethyl-2-dimethyl-2-(dimethylamino)ethyl groups can beexemplified.

As to the alkyl group which may have at least one hydroxy group as thesubstituent, a straight chain-or branched chain-alkyl group having 1 to6 carbon atoms which may have at least one hydroxy group as thesubstituent, there can be exemplified, in addition to theabove-mentioned lower alkyl groups, such as hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropy, 4-hydroxybutyl,5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl and1,1-dimethyl-2-hydroxyethyl groups.

As to the alkyl group which have at least one halogen atom as thesubstituent, a straight chain-or branched chain-alkyl group having 1 to6 carbon atoms which may have 1 to 3 halogen atoms as the substituents,there can be exemplified, in addition to the above-mentioned lower alkylgroups, such as trifluoromethyl, trichloromethyl, chloromethyl,bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloroethyl,1,2-dichloroethyl, 3,3,3-trichloropropyl, 4-fluorobutyl, 5-chloropentyl,3-chloro-2-methylpropyl, 6-bromohexyl, 5,6-dibromohexyl and2,2-dichloropentyl groups.

As the benzoyl group which may have at least one alkoxy group as thesubstituents on the phenyl ring, a benzoyl group which may have 1 to 3straight chain- or branched chain-alkoxy group having 1 to 6 carbonatoms on the phenyl ring, such as benzoyl, 2-methoxybenzoyl,3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl,4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl,3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl, 3,4,5-trimethoxybenzoyl and2,5-dimethoxybenzoyl groups can be exemplified.

As to the lower alkylenedioxy group, a straight chain- or branchedchain-alkylenedioxy group having 1 to 4 carbon atoms in the alkylenemoiety, such as methylenedioxy, ethylenedioxy, trimethylenedioxy andtetramethylenedioxy groups can be exemplified.

As to the cycloalkyl-lower alkyl group, a cycloalkylalkyl group in whichthe cycloalkyl moiety having 3 to 8 carbon atoms and the alkyl moietyhaving 1 to 6 carbon atoms, such as cyclopropylmethyl,2-cyclobutylethyl, 1-cyclopentylethyl, 3-cyclopentylpropyl,4-cyclohexylbutyl, 1,1-dimethyl-2-cycloheptylethyl, 5-cyclooctylpentyl,6-cyclohexylhexyl and 2-methyl-3-cyclohexylpropyl groups can beexemplified.

As to the pyrrolidinylcarbonyl-lower alkyl group, apyrrolidinylcarbonylalkyl group in which the alkyl moiety is a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, such aspyrrolidinylcarbonylmethyl, 2-pyrrolidinylcarbonylethyl,1-pyrrolidinylcarbonylbutyl, 1,1-dimethyl-2-pyrrolidinylcarbonylethyl,3-pyrrolidinylcarbonylpropyl, 4-pyrrolidinylcarbonylbutyl,1,1-dimethyl-2-pyrrolidinylcarbonylethyl, 5-pyrrolidinylcarbonylpentyl,6-pyrrolidinylcarbonylhexyl and 2-methyl-3-pyrrolidinylcarbonyl propylgroups can be exemplified.

The 2,3-dihydro-1H-indene derivatives and salts thereof according to thepresent invention can be prepared by various processes, and some oftypical processes are shown as follows. ##STR3## [wherein R¹, R², R³,R⁴, R⁶ and R⁷ are the same as defined above].

The reaction of a compound of the general formula (2) with hydroxylamine(3) can be carried out in a suitable solvent in the absence or presenceof a basic compound.

As to the basic compound used in this reaction, an inorganic basiccompound such as sodium hydroxide, potassium hydroxide, sodium carbonateor potassium carbonate; an organic basic compound such as piperidine,pyridine, triethylamine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),1,8-diazabicyclo5,4,0]undecene-7 (DBU) or 1,4-diazabicyclo-[2,2,2]octane(DABCO) may be exemplified.

As to the inert solvent used in this reaction, any solvent which doesnot give any adverse effect to the reaction can be used, for examplelower alcohols such as methanol, ethanol and isopropanol; ethers such asdioxane, tetrahydrofuran, diethyl ether and ethylene glycol monomethylether; aromatic hydrocarbons such as benzene toluene and xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and carbon tetrachloride, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide can be exemplified.

The ratio of the amount of hydroxylamine (3) to the amount of a compoundof the general formula (2) may generally be at least an equimolarquantity, preferably an equimolar quantity to 5 times the molar quantityof the former to the latter.

The reaction can be carried out generally at room temperature to 200°C., preferably at 50° to 150° C., and the reaction is completedgenerally within about 1 to 10 hours.

The reduction of a compound of the general formula (101) can be carriedout under conditions similar to those employed in the reduction of acompound of the general formula (104) in the after-cited Reactionprocess formula - 2, preferably can be carried out by catalytichydrogenation in a suitable solvent in the presence of a catalyst.

As to the solvent used in the catalytic hydrogeneration, water, aceticacid, alcohols such as methanol, ethanol, isopropanol; hydrocarbons suchas hexane and cyclohexane; ethers such as diethylene glycol dimethylether, dioxane, tetrahydrofuran and diethyl ether; esters such as ethylacetate and methyl acetate; aprotic polar solvents such asdimethylformamide; and mixed solvent thereof can be exemplified.

As to the catalyst used in this catalytic hydrogenation, palladium,palladium black, palladium-carbon, platinum, platinum oxide, copperchromite and Raney-nickel can be exemplified. The amount of the catalystused in the catalytic hydrogenation, generally 0.02 to 1 time quantitymay be used to the amount of a compound of the general formula (101).The catalytic hydrogenation may be carried out generally at about -20°C. to 100° C., preferably at about 0° C. to 70° C., and generally under1 to 10 atmospheric pressure of hydrogen, the catalytic hydrogenation isgenerally completed within about 0.5 to 20 hours.

When the catalytic hydrogenation of a compound of the general formula(101) wherein R¹, R² or R⁴ is a phenyl group, a phenyl-lower alkyl groupor a pyridinium-lower alkanoylamino-lower alkyl group, is carried outunder the conditions as mentioned above, sometimes a compound of thegeneral formula (102) in which R¹, R² or R⁴ is a cyclohexyl group, acyclohexyl-lower alkyl group or piperidinium-lower alkyl group may beformed. Further the halogen atom in R³ or R⁴ in the general formula(102) may be reduced to change to hydrogen atom. ##STR4## [wherein R¹,R², R³, R⁴, R⁶, R⁷, B and D are the same as defined above; X¹ is ahalogen atom; X is a hydrogen atom or a halogen atom; A' is a loweralkylene group].

The reaction of a compound of the general formula (102) with a compoundof the general formula (4) is carried out in a suitable inert solvent,in the presence of a dehydrohalogenating agent. As to the inert solventused in this reaction, halogenated hydrocarbons such as dichloromethaneand chloroform; ethers such as tetrahdyrofuran and diethyl ether;aromatic hydrocarbons such as benzene, toluene and xylene; esters suchas methyl acetate and ethyl acetate, polar solvents such asdimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide,acetonitrile, acetone, acetic acid, pyridine and water can beexemplified. As to the dehydrohalogenating agent used in this reaction,organic basic compounds such as triethylamine, trimethylamine, pyridine,dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,4-(1-pyrrolidinyl)pyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),1,8-diazabicyclo[5,4,0]undecene-7 (DBU), 1,4-diazabicyclo[2,2,2]octane(DABCO) and sodium acetate; and inorganic basic compounds such aspotassium carbonate, sodium carbonate, potassium bicarbonate, sodiumbicarbonate, potassium hydroxide and sodium hydroxide can beexemplified.

The ration of the amount of a compound of the general formula (4) to theamount of a compound of the general formula (102) may be generally atleast an equimolar quantity, preferably an equimolar quantity to 2 timesthe molar quantity of the former to the latter. The reaction is carriedout generally about at -20° C. to 150° C., preferably about at 0° C. to100° C., and is completed within about 5 minutes to 7 hours. Thus, acompound of the general formula (103) is prepared.

In the case of using a compound of the general formula (103) in which Xis a halogen atom, a compound of the general formula (104) can beintroduced by reacting such compound of the general formula (103) with acompound of the general formula (5). The reaction of the compound of thegeneral formula (103) with a compound of the general formula (5) iscarried out in a suitable inert solvent in the presence of adehydrohalogenating agent. As to the inert solvent used in thisreaction, alcohols such methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve; ethers suchas tetrahydrofuran, diethyl ether; aromatic hydrocarbons such asbenzene, toluene, xylene; aprotic polar solvents such as acetone,acetonitrile, dimethylformamide, dimethyl sulfoxide andhexamethylphosphoric triamide; halogenated hydrocarbons such asmethylene chloride, dichloroethane and chloroform; esters such as methylacetate and ethyl acetate; and mixed solvents thereof can beexemplified. As to the dehydrohalogenating agent used in this reaction,usual basic compounds for example, organic basic compounds such astriethylamine, trimethylamine, pyridine, dimethylaniline,N-methylmorpholine, 4-dimethylaminopyridine, 4-(1-pyrrolidinyl)pyridine,DBN, DBU, DABCO and sodium acetate; inorganic basic compounds such aspotassium carbonate, sodium carbonate, potassium bicarbonate, sodiumbicarbonate, potassium hydroxide, sodium hydroxide, potassium hydride,sodium hydride and sodium amide; alkali metal alcoholates such as sodiummethylate and sodium ethylate, can be exemplified.

The ratio of the amount of a compound of the formula (5) to the amountof a compound of the general formula (103) may be generally at least anequimolar quantity, preferably an equimolar quantity to 3 times themolar quantity of the former to the latter. Further, an excess amount ofa compound of the formula (5) may also be used as thedehydrohalogenating agent.

The reaction is generally carried out about at 0° C. to 120° C.,preferably about room temperature to 100° C., and is completed withinabout 0.5 to 10 hours. Thus compound of the general formula (104) can beobtained.

In some cases, a compound of the general formula (120), ##STR5## mayalso be obtained in the above-mentioned reaction under similarconditions. The compound of the general formula (120) and the compoundof the general formula (104) can easily be separated from each other byusual separating means.

The reaction for obtaining a compound of the general formula (105) byreducing a compound of the general formula (104) can be carried out byvarious method, for example, the reduction conditions of a compound ofthe general formula (101) employed in the above-mentioned Reactionprocess formula - 1, preferably, reduction by using hydrogenating agentmay be employed. As to the hydrogenating agent, lithium aluminumhydride, sodium boron hydride and diborane can be exemplified. The ratioof the amount of said hydrogenating agent to the amount of a compound ofthe general formula (104) is generally at least an equimolar quantity,preferably about an equimolar quantity to 10 times the molar quantity ofthe former to the latter. The reduction is generally carried out in asuitable solvent, for example water, lower alcohol such as methanol,ethanol or isopropanol; ether such as tetrahydrofuran, diethyl ether ordiglyme; or acetic acid, and generally at about 0° to 200° C.,preferably about at 0° to 170° C., for about 10 minutes to 10 hours. Incase of using lithium aluminum hydride or diborane as the reducingagent, an anhydrous solvent such as diethyl ether, tetrahydrofuran ordiglyme may be used. ##STR6## [wherein R¹, R², R³, R⁴, R⁶, R⁷, X¹, A'and B are the same as defined above].

The reaction of a compound of the general formula (102) with a compoundof the general formula (6) can be carried out under conditions similarto those employed in the reaction of a compound of the general formula(102) with a compound of the general formula (4) in the above-mentionedReaction process formula - 2. ##STR7## [wherein R¹, R², R³, R⁴, R⁶, R⁷,A' and B are the same as defined above; Z is a group of the formulaprovided that the number of carbon atoms in a group of the formula##STR8## should not be exceeded 6].

The reaction of a compound of the general formula (102) with a compoundof the general formula (7) is carried out with or without in a suitablesolvent, in the presence of a basic compound. As to the solvent used inthis reaction, ethers, such as dioxane, tetrahydrofuran and ethyleneglycol diethyl ether; aromatic hydrocarbons such as benzene toluene andxylene; alcohols such as methanol, ethanol and isopropanol; aproticpolar solvents such as acetone, acetonitrile, dimethylformamide,dimethyl sulfoxide and hexamethylphosphoric triamid can be exemplified.As to the basic compound used in the reaction, inorganic basic compoundssuch as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, sodium bicarbonate and sodium amide; organic basiccompounds such as triethylamine, tripropylamine, pyridine, quinoline,DBN, DBU and DABCO can be exemplified. The ratio of the amount of acompound of the general formula (7) to the amount of a compound of thegeneral formula (102) may be generally at least an equimolar quantity,preferably an equimolar quantity to 5 times the molar quantity of theformer to the latter. The reaction is carried out generally at about 0°C. to 200° C., preferably at about 50° to 10° C., and is completedwithin about 1 to 12 hours. ##STR9## [wherein R¹, R², R³, R⁴, R⁶ and R⁷are the same as defined above; and R⁹ is a halogen-substituted loweralkanoyl group].

The reaction of a compound of the general formula (102) with a compoundof the general formula (8) is carried out by an usual method of amidebond formation reaction. In carrying out said amide bond formationreaction, an activated compound of a carboxylic acid of the generalformula (8) may be used. As to the amide bond formation reaction,reaction conditions usually employed in amide bond formation reactioncan be used. For example, (a) a mixed acid anhydride method, i.e., byreacting a carboxylic acid of the general formula (8) with analkylhalocarboxylic acid to form the corresponding mixed acid anhydride,then a compound of the general formula (102) is reacted therewith; (b)an activated ester method or activated amide method, i.e., by convertinga carboxylic acid of the general formula (8) into the correspondingactivated ester such as p-nitrophenyl ester, N-hydroxysuccinimide esteror 1-hydroxybenzotriazol ester, or into the corresponding activatedamide such as benzoxazolin-2-thion, then a compound of the generalformula (102) is reacted with said activated ester or with saidactivated amide; (c) a carbodiimide method, i.e., by condensing acarboxylic acid of the general formula (8) with a compound of thegeneral formula (102) in the presence of a dehydrating agent such asdicyclohexylcarbodiimide or carbonyl diimidazol; (d) a carboxylic acidhalide method, i.e., by converting a carboxylic acid of the generalformula (8) into the corresponding halide, then a compound of thegeneral formula (102) is reacted therewith; (e) other method, acarboxylic acid anhydride method, i.e., by converting a carboxylic acidof the general formula (8) into the corresponding carboxylic acidanhydride by using dehydrating agent such as acetic anhydride, then acompound of the general formula (102) is reacted therewith; and (f) ahigh pressure-high temperature methode, i.e., by reacting an esterprepared from a carboxylic acid of the general formula (8) with a loweralcohol, with a compound of the general formula (102) under a highpressure at a high temperature, can be exemplified. Further, othermethod, (g) by activating a carboxylic acid of the general formula (8)with a phosphorus compound such as triphenylphosphine ordiethylchlorophosphate, then a compound of the general formula (102) isreacted with said activated carboxylic acid, can be employed.

As to the alkylhalocarboxylic acid used in the above-mentioned (a) mixedacid anhydride method, methyl chloroformate, methyl bromoformate, ethylchloroformate, ethyl bromoformate and isobutyl chloroformate can beexemplified. The mixed acid anhydride is prepared by an usualSchotten-Baumann reaction, and generally, said mixed acid anhydride maybe used without isolated, and reacted with a compound of the generalformula (102) to prepare a compound of the general formula (1).Schotten-Baumann reaction is generally carried out in the presence of abasic compound. As to the basic compound used in the reaction, any basiccompound used conventionally in Schotten-Baumann reaction may be used,for example organic basic compounds such as triethylamine,trimethylamine, pyridine, dimethylaniline, N-methylmorpholine,4-dimethylaminopyridine, DBN, DBU and DABCO; and inorganic basiccompounds such as potassium carbonate, sodium carbonate, potassiumbicarbonate and sodium bicarbonate can be exemplified. The reaction iscarried out at about -20° C. to 100° C., preferably at about 0° C. to50° C., for about 5 minutes to 10 hours, preferably for about 5 minutesto 2 hours. The reaction of thus obtained mixed acid anhydride with acompound of the general formula (102) is carried out at about -20° C.,to 150° C., preferably at about 10° to 50° C., for about 5 minutes to 10hours, preferably for about 5 minutes to 5 hours. The reaction of mixedacid anhydride may not specifically be carried in a solvent, butgenerally is carried out in a solvent. As to the solvent used in thereaction, any solvent employed conventionally in the mixed acidanhydride method can be used, and specifically, halogenated hydrocarbonssuch as metylene chloride, chloroform and dichloroethane; aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, diisopropyl ether, tetrahydrofuran and dimethoxyethane; esterssuch as methyl acetate and ethyl acetate; aprotic polar solvents such asdimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamidecan be exemplified. The ratios of the amount of a carboxylic acid of thegeneral formula (8), the amount of an alkylhalocarboxylic acid and theamount of a compound of the general formula (102) are generally at leastan equimolar quantity of each, and preferably 1 to 2 times the molarquantity each of an alkylhalocarboxylic acid and a compound of thegeneral formula (102) may be used to a carboxylic acid of the generalformula (8).

In carrying out the above-mentioned (b) an activated ester method or anactivated amide method, in case of using benzoxazolin-2-thionamide, thereaction is carried out in a suitable solvent which does not give anyadverse effect to the reaction, for example a solvent similar to thatused in the above-mentioned mixed acid anhydride methode, and furtherusing 1-methyl-2-pyrrolidone, at about 0° C. to 150° C., preferably atabout 10° to 100° C., for 0.5 to 75 hours. The ratio of the amount of acompound of the general formula (102) to the amount ofbenzoxazolin-2-thionamide is generally at least an equimolar quantity,preferably an equimolar to 2 times the molar quantity of the latter isused to the former. In case of using N-hydroxysuccinimide ester, thereaction is carried out advantageously by using a suitable basiccompound similar to that employed in the after cited (d) carboxylic acidhalide method.

In carrying out the above-mentioned (d) carboxylic acid halide method,the reaction is conducted by reacting a carboxylic acid of the generalformula (8) with a halogenating agent to prepare the correspondingcarboxylic acid halide, then said carboxylic acid halide is isolated andpurified from the reaction system or without isolated and purified, thenis reacted with a compound of the general formula (102). The reaction ofsaid carboxylic acid halide with a compound of the general formula (102)is carried out in a suitable solvent in the presence of adehydrohalogenating agent. As to the dehydrohalogenating agent used inthe reaction, generally a basic compound is used, and other than thebasic compounds used in the above-mentioned Schotten-Baumann reaction,sodium hydroxide, potassium hydroxide, sodium hydride, potassiumhydride, silver carbonate, an alkali metal alcoholate such as sodiummethylate or sodium ethylate can be exemplified. Further, an excessamount of a compound of the general formula (102) can also be used asthe dehydrohalogenating agent. As to the solvent used in this reaction,other than the solvents used in the above-mentioned Schotten-Baumannreaction, water, alcohols such as methanol, ethanol, propanol, butanol,3-methoxy-1-butanol and ethyl cellosolve; pyridine, acetone, andacetonitrile; and mixed solvents of at least 2 or more of theabove-mentioned solvents can be exemplified. The ratio of the amount ofa carboxylic acid of the general formula (102) to the amount of saidcarboxylic acid halide is not restricted within the specific range, andcan be selected from a wide range, generally at least an equimolarquantity, preferably an equimolar to 2 times the molar quantity of thelatter is used to the former. The reaction is generally carried out atabout -30° C. to 180° C., preferably at about 0° C. to 150° C., and iscompleted generally in about 5 minutes to 30 hours. The carboxylic acidhalide is prepared by reacting a carboxylic acid of the general formula(8) with a halogenating agent in the presence or absence of a solvent.As to the solvent, any solvent which does not give any adverse effect tothe reaction can be used, for example aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such aschloroform, methylene chloride, and carbon tetrachloride; ethers such asdioxane, tetrahydrofuran, and diethyl ether; dimethylformamide anddimethyl sulfoxide can be exemplified. As to the halogenating agent, ausual halogenating agents which can be able to convert the hydroxylgroup in carboxy group into halogen atoms can be used, for examplethionyl chloride, phosphorus oxychloride, phosphorus oxybromide,phosphorus pentachloride and phosphorus pentabromide can be exemplified.Ratio of the amount of carboxylic acid (8) to the amount of halogenatingagent is not specifically restricted, and can be selected from a widerange. In the case of carrying out the halogenation in the absence ofsolvent, a large excess amount of the latter is used to the former.While, when the halogenation is carried out in the presence of asolvent, at least an equimolar quantity, preferably 2 to 4 times themolar quantity of the latter is used to the former. The reactiontemperature and the reaction time may not be specifically restricted,and generally the reaction is carried out at about room temperature to100° C., preferably at about 50° to 80° C., for about in 30 minutes to 6hours.

In carrying out the above-mentioned method (g) in which a carboxylicacid (8) is activated by using a phosphorus compound such astriphenylphosphine or diethylchlorophosphate, the reaction is carriedout in a suitable solvent. As to the solvent used in this reaction, anyinert solvent which does not give any adverse effect to the reaction canbe used, for example halogenated hydrocarbons such as methylenechloride, chloroform and dichloroethane; aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran and dimethoxyethane; esters such as methyl acetate andethyl acetate; aprotic polar solvents such as dimethylformamide,dimethyl sulfoxide and hexamethylphosphoric triamide can be exemplified.In this reaction, since a compound (102) per se acts as the basiccompound, the reaction is proceeded advantageously by using saidcompound (102) in an amount over stoichiometric quantity. If necessary,other basic compounds, for example organic basic compounds such astriethylamine, trimethylamine, pyridine, dimethylaniline,N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU and DABCO; andinorganic basic compounds such as potassium carbonate, sodium carbonate,potassium bicarbonate and sodium bicarbonate can be used. The reactionis achieved at a temperature of 0° C. to 150° C., preferably at about 0°C. to 100° C., for about in 1 to 30 hours. Ratios of the amounts of thephosphorus compound and a carboxylic acid (8) to the amount of acompound (102) are generally at least equimolar quantities, preferablyequimolar to 3 times the molar quantity, respectively. ##STR10##[wherein R¹, R², R³, R⁴, R⁶, R⁷, B, D, l and X¹ are the same as definedabove].

The reaction of a compound (102) with a compound (9) can be carried outunder conditions similar to those employed in the reaction of a compound(102) with a compound (4) in the above-mentioned Reaction processformula - 2.

The compounds (102) used as the starting materials in theabove-mentioned Reaction process formulas - 1, - 2, - 4, - 5 and -6contain novel compounds, and are prepared through the following methods.##STR11## [wherein R¹, R², R³, R⁶ and X¹ are the same as defined above;and R¹⁰, R¹¹, R²³ and R²⁴ are each a hydrogen atom, a lower alkyl group,a phenyl group or a cycloalkyl group].

The reaction of a compound of the general formula (201) with a compoundof the general formula (10) is carried out in the presence of a basiccompound. As to the basic compound used in this reaction, any knownbasic compound can be used, for example inorganic basic compounds suchassodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium bicarbonate, potassium bicarbonate and silvercarbonate; alkali metals such as sodium metal and potassium metal;alkali metal clcoholates such as sodium methylate and sodium ethylene;organic basic compounds such as triethylamine, pyridine,N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN,DBU and DABCO can be exemplified. The reaction is carried out without orin a solvent. As to the solvent used in this reaction, any inert solventwhich does not give any adverse effect to the reaction can be used, forexample water, alcohols such as methanol, ethanol, propanol, butanol,ethylene glycol; ethers such as dimethyl ether, tetrahydrofuran,dioxane, monoglyme and diglyme; ketones such as acetone, methyl ethylketone; aromatic hydrocarbons such as benzene, toluene and xylene;esters methyl acetate and ethyl acetate; aprotic polar solvents such asN,N-methylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide;and mixed solvents thereof can be exemplified. Further, the reaction isadvantageously carried out in the presence of a metal iodide such assodium iodide or potassium iodide.

Ratio of the amount of a compound of the general formula (201) to theamount of a compound of the general formula (8) is not specificallyrestricted, and can be selected from a wide range, generally anequimolar quantity to 5 times the molar quantity, preferably anequimolar quantity to 2 times the molar quantity of the latter is usedto the former. The reaction temperature is also not specificallyrestricted, and generally the reaction is carried out within roomtemperature to 200° C., preferably at 50° to 150° C., and the reactiontime is generally in 1 to 30 hours, preferably in 1 to 15 hours.

The reaction for obtaining a compound of the general formula (203) froma compound of the general formula (202) is generally called as "ClaisenRearrangement", and can be carried out by heating a compound of thegeneral formula (202) in a suitable solvent to introduced to a compoundof the general formula (203). As to the solvent used in thisrearrangement reaction, a solvent having higher boiling point such asdimethylformamide and tetrahydronaphthalene can be exemplified. Therearrangement reaction is generally carried out at 100° to 250° C.,preferably at 150° to 250° C., and is completed in 1 to 20 hours.##STR12## [wherein R¹, R², R³, R⁶ and R⁷ are the same as defined above;R¹² is a lower alkanoylamino-lower alkyl group having halogen atoms asthe substituents; and R¹³ is a pyridinium-lower alkanoylamino-loweralkyl group or piperidinyl-lower alkanoylamino-lower alkyl group].

The reaction of a compound of the general formula (201) with a compoundof the general formula (10) is carried out in the presence of adehydro-condensing agent, without or in a suitable solvent. As to thedehydro-condensing agent used in this reaction, condensed phosphoricacids such as polyphosphoric acids; phosphoric acids such asorthophosphoric acid, pyrophosphoric acid, metaphosphoric acid;phosphorous acids such as orthophosphorous acid; phosphoric acidanhydrides such as phosphorous pentoxide; mineral acids such ashydrochloric acid, sulfuric acid, boric acid; metal phosphates such assodium phosphate, boron phosphate, ferric phosphate and aluminumphosphate; activated alumina, sodium bisulfate and Raney-nickel can beexemplified. As to the solvent used in this reaction, dimethylformamideand tetrahydronaphthalene can be exemplified.

Ratio of the amount of a compound of the general formula (201) to theamount of a compound of the general formula (10) is not specificallyrestricted, and can be selected from a wide range, and generally anequimolar quantity, preferably an equimolar to 2 times the molarquantity of the latter is used to the former. The amount of thedehydro-condensing agent is not restricted specifically, and can beselected from a wide range, generally a catalytic amount, preferably alarge excess amount thereof may be used to a compound of the generalformula (201). The reaction is generally advantageously carried out at-30° to 50° C., preferably at about 0° C. to room temperature, and iscompleted in about 1 to 30 hours.

The reaction of a compound of the general formula (204) with pyridine orpiperidine can be carried out under conditions similar to those employedin the reaction of a compound of the general formula (102) with acompound of the general formula (4).

Both compound of the general formula (6) and compound of the generalformula (9) include novel compounds and can be prepared by, for examplethe following processes. ##STR13## [wherein X, X¹, X², A, l, D and B arethe same as defined above].

Both reaction of a compound (11) with a compound (5) and reaction of acompound (4) with a compound (5) can be carried out under conditionssimilar to those employed in the reaction of a compound (102) with acompound (4) in the above-mentioned Reaction process formula - 2.

Compound represented by the general formula (7) contain some novelcompounds, and they can be prepared by methode for example the followingprocess. ##STR14## [wherein X¹, A', Z and B are the same as definedabove].

The reaction of a compound (12) with a compound (5) is carried out in asuitable solvent or without the solvent in the presence of a basiccompound. As to the basic compound inorganic basic materials such assodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallicsodium and metallic potassium; and organic basic compounds such aspiperidine, pyridine, triethylamine, DBN, DBU and DABCO can beexemplified. As to the solvent used in this reaction, ketones such asacetone and methyl ethyl ketone; ethers such as diethyl ether, dioxaneand diethylene glycol dimethyl ether; aromatic hydrocarbons such asbenzene, toluene and xylene; acetonitrile and water can be exemplified.Furthermore, a compound (12) may be used as the solvent. Ratio of theamount of a compound (12) to the amount of a compound (5) may begenerally an excess quantity, preferably 5 to 10 times the molarquantity of the former to the latter. The reaction is carried outgenerally at about 0° C. to 150° C., preferably 50° to 100° C., and isfinished generally within 1 to 12 hours. ##STR15## [wherein R¹, R², R³,R⁴, R⁶ and X¹ are the same as defined above].

The Fries rearrangement subsequent cyclization reaction of a compound ofthe general formula (206) to form a compound of the general formula(207) can be carried out in the presence of an acid, in a suitablesolvent or without the solvent. As to the acid used in the reaction,aluminum chloride, zinc chloride, iron chloride, tin chloride, borntrifluoride, born tribromide and concentrated sulfuric acid can beexemplified. As to the solvent used in this reaction, carbon disulfide,aromatic hydrocarbons such as nitrobenzene, chlorobenzens; halogenatedhydrocarbons such as dichloromethane, dichloroethane, trichloroethaneand tetrachloroethane can be exemplified. The amount of the Lewis acidto be used may be determined properly, and generally at least anequimolar quantity, preferably an equimolar quantity to 6 times themolar quantity thereof is used to a compound of the general formula(206). The Fries rearrangement subsequent cyclization reaction isgenerally carried out at room temperature to 200° C., preferably atabout 50° to 180° C., for about 10 minutes to 7 hours. ##STR16##[wherein R¹, R³, R⁴ and R⁶ are the same as defined above].

The Fries rearrangement subsequent cyclization of a compound of thegeneral formula (208) can be carried out under conditions similar tothose employed in the cyclization of a compound of the general formula(206) in the above-mentioned Reaction process formula - 11. ##STR17##[wherein R¹, R³, R⁴, R⁶ and R⁷ are the same as defined above].

The cyclization of a compound of the general formula (211) can becarried out in the presence of an acid, in a suitable solvent. As to theacid used in this reaction, inorganic acids such as hydrochloric acid,sulfuric acid, hydrobromic acid; organic acids for example alkanoicacids such as acetic acid, trifluoroacetic acid and other organic acidssuch as p-toluenesulfonic acid can be exemplified. As to the solventused in this cyclization, alcohols such as methanol, ethanol andisopropanol; aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and carbon tetrachloride; ethers such as diethyl ether,tetrahydrofuran, dioxane, diglyme and monoglyme; aprotic polar solventssuch as dimethylformamide, dimethyl sulfoxide and hexamethylphosphorictriamide can be exemplified. The cyclization can be carried out,generally at about 0° to 150° C., preferably at about 0° to 100° C., forabout 30 minutes to 24 hours to complete the reaction.

The reaction for introducing a compound of the general formula (212) toa compound of the general formula (213) can be carried out by treatingthe former in a suitable solvent, for example water, a lower alcoholsuch as methanol, ethanol or isopropanol; an ether such as dioxane ortetrahydrofuran; or acetic acid; or a mixed solvent thereof, in thepresence of a catalytic reduction catalyst such as palladium-carbon orpalladium-black, at a temperature of about 0° to 100° C., under 1 to 10atmospheric pressure of hydrogen gas, for 0.5 to 3 hours, or by heattreating a compound of the general formula (212) with a mixture of anacid such as hydrobromic acid or hydrochloric acid and a solvent such aswater, methanol, ethanol or isopropanol, at a temperature of 30° to 150°C., preferably at 50° to 120° C., to introduce a compound of the generalformula (213).

Furthermore, a compound of the general formula (213) can also beobtained by hydrolyzing a compound of the general formula (212). Thishydrolysis can be carried out in a suitable solvent in the presence ofan acid or basic compound. As to the solvent used in this hydrolysis,water, lower alcohols such as methanol, ethanol and isopropanol; ethersdioxane and tetrahydrofuran; aprotic polar solvents such asacetonitrile; and mixtures of these solvents can be exemplified. As tothe acid used in this hydrolysis, mineral acids such as hydrochloricacid, hydrobromic acid and sulfuric acid; Lewis acids such as aluminumchloride; metal iodides such as sodium iodide and potassium iodided; andmixtures of the Lewis acid with the iodide can be exemplified. As to thebasic compound used in the hydrolysis, metal hydroxides such as sodiumhydroxide, potassium hydroxide and calcium hydroxide can be exemplified.The hydrolysis can advantageously be carried out generally at roomtemperature to 150° C., preferably at room temperature to 100° C., andcompleted in 0.5 to 15 hours. ##STR18## [wherein R³, R⁴, R⁶ and X¹ arethe same as defined above; R¹⁶ is a lower alkyl group; R¹⁷ and R¹⁸ areeach a lower alkyl group, a cycloalkyl group, an unsubstitutedphenyl-lower alkyl group or a substituted phenyl-lower alkyl grouphaving halogen atoms and/or lower alkyl groups as the substituents onthe phenyl ring].

The reaction of a compound of the general formula (214) with a compoundof the general formula (16) is carried out in a suitable solvent in thepresence of a basic compound. As to the basic compound used in thereaction, sodium hydroxide, potassium hydroxide, sodium ethylate, sodiumhydride, potassium hydride, sodium amide and potassium amide can beexemplified. As to the solvent, alcohols such as methanol, ethanol andisopropanol; ethers such as dioxane and diethylene glycol dimethylether; aromatic hydrocarbons such as benzene, toluene and xylene;aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide andhexamethylphosphoric triamide can be exemplified. The amount of acompound of the general formula (16) is not specifically restricted andcan be selected from a wide range, generally, at least an equimolarquantity, preferably an equimolar to 5 times the molar quantity thereofmay be used to a compound of the general formula of (214). The reactionis generally carried out at about 0° to 70° C., preferably at about 0°C. to room temperature, and is completed in 0.5 to 12 hours.

The reaction of a compound of the general formula (215) in which R¹ andR² are hydrogen atoms with a compound of the general formula (17), andthe reaction of a compound (216) with a compound of the general formula(16) can be carried out under conditions similar to those employed inthe reaction of a compound of the general formula (214) with a compoundof the general formula (16).

A compound of the general formula (218) can be prepared from a compoundof the general formula (217) under conditions similar to those employedin the reaction for obtaining a compound of the general formula (212).##STR19## [wherein R³, R⁴, R⁶, R⁷ and R¹⁷ are same as defined above; R¹⁹is an unsubstituted phenyl-lower alkyl group or a substitutedphenyl-lower alkyl group having halogen atoms and/or lower alkyl groupsas the substituents of the phenyl ring].

The reaction of a compound of the general formula (219) with a compoundof the general formula (19) can be carried out in a suitable solvent orwithout the solvent, in the presence of a basic compound. As to thesolvent used in the reaction, any solvent which does not give adverseeffect to the reaction can be used, for example water, alcohols such asmethanol, ethanol and isopropanol; aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran, dioxane, diglyme and monoalyme; halogenatedhydrocarbons such as dichloromethane, chloroform and carbontetrachloride; aprotic polar solvents such as dimethylformamide,dimethyl sulfoxide and hexamethylphosphoric triamide can be exemplified.As to the basic compound used in the reaction, inorganic basic compoundssuch as sodium hydroxide, potassium hydroxide, potassium carbonate,sodium carbonate, potassium bicarbonate, sodium bicarbonate and sodiumhydride; metal alcoholates such as sodium ethylate and sodium methylate;organic basic compounds such as 1,5-diazabicyclo[4,3,0]non-5-ene (DBN),1,8-diazabicyclo-[5,4,0]undec-7-ene (DBU) and1,4-diazabicyclo[2,2,2]octane (DABCO) and triethylamine can beexemplified.

The amount of the compound of the general formula (19) may be at leastan equimolar, preferably an equimolar to 2 times the molar quantitythereof used to a compound of the general formula (219). As to theamount of the basic compound, at least an equimolar quantity, preferablyan equimolar to 5 times the molar quantity thereof used to a compound ofthe general formula (219). The reaction is generally carried out atabout 0° to 150° C., preferably at about room temperature to 100° C.,and is completed in about 0.5 to 8 hours.

The reduction of a compound of the general formula (220) can be carriedout under the conditions similar to those employed in the reduction of acompound of the general formula (101) in the above-mentioned Reactionprocess formula-1.

The reaction of a compound of the general formula (221) with a compoundof the general formula (17) can be carried out under conditions similarto those employed in the reaction of a compound of the general formula(215) with a compound of the general formula (17), except the reactiontemperature, that at generally about 0° to 90° C., preferably at about0° to 60° C. ##STR20## [wherein R¹, R², R⁶ and R⁷ are the same asdefined above; R^(3') and R^(3") are the same as defined in R³ ; R^(4')and R^(4") are the same as defined in R⁴ ; provided that at least anyone of R^(3') and R^(4') is a hydrogen atom, and at least any one ofR^(3") and R^(4") is a halogen atom].

The halogenation of a compound of the general formula (222) can becarried out in a suitable solvent, in the presence of a usualhalogenating agent. As to the halogenating agent, any one used can beapplied, for example halogen molecule such as bromine and chlorine;iodine monochloride, sulfuryl chloride, N-halogenosuccinimides such asN-bromosuccinimide and N-chlorosuccinimide can be exemplified. Theamount of halogenating agent may be generally an equimolar to 10 timesthe molar quantity, preferably an equimolar to 5 times the molarquantity thereof to a compound of the general formula (222). As to thesolvent used in the halogenation, halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform and carbon tetrachloride;fatty acids such as acetic acid and propionic acid; and water can beexemplified. The halogenation is generally carried out at 0° C. to theboiling point of the solvent, preferably at about 0° to 40° C., and iscompleted in about 1 to 10 hours.

A compound of the general formula (211) being used as the startingmaterial in the above-mentioned Reaction process formula - 13 can beprepared by a methode as shown in the following Reaction process formula##STR21## [wherein R¹, R³ and R⁴ are the same as defined above; andR^(6') is a phenyl group].

The reaction of a compound of the general formula (224) with a compoundof the general formula (20) can be carried out under conditions similarto those employed in the reaction of a compound of the general formula(219) with a compound of the general formula (19).

Process for introducing a compound of the general formula (224) to acompound of the general formula (211b) can be conducted by the followingmethods.

(i) Method for reacting a compound of the general formula (224) with acompound of the general formula ##STR22## (wherein R²⁵ and R²⁶ are eacha lower alkyl group) and with formaldehyde, which is called as "MannichReaction".

This reaction can be carried out in a suitable solvent in the presenceof an acid. As to the solvent used in the reaction, any solvent whichcan be generally used in Mannich reaction can also be used, for examplewater, alcohols such as methanol, ethanol and isopropanol; alkanoicacids such as acetic acid and propionic acid; acid anhydrides such asacetic anhydride; polar solvents such as acetone and dimethylformamide;and mixed solvents thereof can be exemplified. As to the acid used inthe reaction, mineral acids such as hydrochloric acid and hydrobromicacid; organic acids such as acetic acid can be exemplified. As to theformaldehyde used in the reaction, as aqueous solution of formaldehydecontaining 20 to 40% by weight thereof, trimer of formaldehyde orparaformaldehyde can be used. The amount of a compound of the generalformula ##STR23## is at least an equimolar quantity, preferably anequimolar to 2 times the molar quantity may be used to a compound of thegeneral formula (224). The amount of formaldehyde is at least asequimolar quantity, generally a large excess quantity may be used to acompound of the general formula (224). The reaction is generally carriedout at about 0° to 200° C., preferably at about room temperature to 150°C., and is completed in 0.5 to 10 hours.

(ii) Method for reaction a compound of the general formula (224) with acompound of the general formula ##STR24## (wherein R²⁵ and R²⁶ are thesame as defined above).

This reaction can be carried out in the presence of an acid in asuitable solvent or without the solvent. As to the acid used int hereaction, mineral acids such as sulfuric acid, hydrochloric acid andhydrobromic acid; organic acids such as acetic acid and acetic anhydridecan be exemplified, preferably, acetic anhydride may be used. As to thesolvent used in the reaction, any solvent which can be used in theabove-mentioned Mannich reaction can also be used. The amount of acompound of the general formula ##STR25## may be at least an equimolarquantity, preferably an equimolar to 5 times the molar quantity to theamount of a compound of the general formula (224). The reaction iscarried out generally at 0° to 150° C., preferably at about roomtemperature to 100° C., and is completed in about 0.5 to 5 hours.##STR26## [wherein R¹, R³, R⁴, R⁶, R⁷ and X¹ are the same as definedabove; R¹⁴ is an alkyl group having 7 to 10 carbon atoms, a loweralkenyl group, a lower alkylamino-lower alkyl group, a phenyl-loweralkyl group, or a group of the formula --A"--B (wherein A" is a loweralkylene group which may have hydroxyl groups as the substituents; B isthe same as defined above)].

The reaction of a compound of the general formula (102) with a compoundof the general formula (13) can be carried out under conditions similarto those employed in the reaction of a compound of the general formula(102) with a compound of the general formula (4) in the above-mentionedReaction process formula - 2. ##STR27## [wherein R¹, R², R³, R⁴ and R⁷are the same as defined above; R¹⁵ is a lower alkenyl group, a loweralkylaminolower alkyl group, a phenyl-lower alkyl group, a lower alkylgroup having 7 to 10 carbon atoms].

The reaction of a compound of the general formula (2) with a compound ofthe general formula (14) is carried out in a suitable solvent or withoutthe solvent, in the presence or absence of a dehydrating agent. As tothe solvent used in the reaction, alcohols such as methanol, ethanol andisopropanol; aromatic hydrocarbons such as benzene, toluene xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and carbon tetrachloride; aprotic polar solvents such asdimethylformamide, dimethylacetamide and N-methylpyrrolidone; andmixtures of these solvents can be exemplified. As to the dehydratingagent drying agents which can be used for dehydrating usual solvent suchas molecular sieves, mineral acids such as hydrochloric acid, sulfuricacid and boron trifluoride; organic acids such as p-toluenesulfonic acidcan be exemplified.

The reaction is generally carried out at room temperature to 250° C.,preferably at about 50° to 200° C. and is completed generally in about 1to 48 hours. The amount of a compound of the general formula (14) is notspecifically restricted, and generally at least an equimolar quantity,preferably an equimolar to a large excess quantity thereof may be usedto a compound of the general formula (2). As to the amount of thedehydrating agent, in case of using a drying agent a large excessquantity thereof may be used, and in case of using an acid a catalyticamount of acid may be used. A compound of the general formula (111) thusobtained is subjected to the next reducing reaction without isolatedfrom the reaction system.

In carrying out the reducing reaction of a compound of the generalformula (111), various methods can be applied, for example, the methodfor reducing a compound of the general formula (101) in theabove-mentioned Reaction process formula-1 can be applied, preferably amethod by using a hydrogenating reducing agent can be applied. As to thehydrogenating reducing agent, lithium aluminum hydride, sodium boronhydride and diborane can be exemplified. The amount of the hydrogenatingreducing agent used in the reduction is at least an equimolar quantity,preferably an equimolar to 10 times the molar quantity thereof to acompound of the general formula (111). In the case of using lithiumaluminum hydride as the reducing agent, 2 times the molar quantitythereof may advantageously be used to a compound of the general formula(111). This reducing reaction is generally carried out in a suitablesolvent for example, water, lower alcohols such as methanol, ethanol andisopropanol; ethers such as tetrahydrofuran, diethyl ether and diglyme,and generally at about -60° to 50° C., preferably at about - 30° C. toroom temperature, for about 10 minutes to 5 hours. Furthermore, in thecase of using lithium aluminum hydride or diborane as the reducingagent, an anhydrous solvent such as diethyl ether, tetrahydrofuran ordiglyme may be used. ##STR28## [wherein R¹, R², R⁵, R⁶, R^(3'), R^(4'),R^(3") and R^(4") are the same as defined above].

The halogenation of a compound of the general formula (115) can becarried out under conditions those employed in the halogenation of acompound of the general formula (222) in the above-mentioned Reactionprocess formula - 16. ##STR29## [wherein R¹, R³, R⁴, R⁶, R⁷ and R¹⁵ arethe same as defined above].

The reaction of a compound of the general formula (212) with a compoundof the general formula (14) is carried out in a suitable solvent, in thepresence of a dehydrating agent. As to the solvent used in the reaction,alcohols such as methanol, ethanol and isopropanol; aromatichydrocarbons such as benzene, toluene and xylene; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform andcarbon tetrachloride; aprotic polar solvents such as dimethylformamide,dimethylacetamide and N-methylpyrrolidone, and mixtures of thesesolvents can be exemplified. As to the dehydrating agent, drying agentsused for dehydrating usual solvents such as molecular sieves, mineralacids such as hydrochloric acid, sulfuric acid and boron trifluoride;organic acids such as p-toluenesulfonic acid can be exemplified. Thereaction is generally carried out at about 0° to 150° C., preferably atabout at room temperature to 100° C., and is completed in about 1 to 48hours. The amount of a compound of the general formula (14) used in thereaction is not particularly restricted, and generally at least anequimolar quantity, preferably an equimolar to 2 times the molarquantity thereof may be used to a compound of the general formula (212).The amount of the dehydrating agent used in the reaction, in the case ofusing a drying agent as the dehydrating agent, generally a large excessamount thereof is used, and in the case of using an acid as thedehydrating agent, generally a catalytic amount thereof may be used.

The reducing reaction of a compound of the general formula (225) can becarried out under conditions similar to those employed in the reducingreaction of a compound of the general formula (101) in theabove-mentioned Reaction process formula - 1. In some cases, when acompound of the general formula (225) wherein R¹⁵ is a phenyl-loweralkyl group, a compound represented by the general formula (118)##STR30## [wherein R^(A) is a phenyl-lower alkyl group]. may also beobtained under the above-mentioned reducing conditions. The compound ofthe general formula (118) and a compound of the general formula (117)can easily be separated by usual separating means.

The desired products prepared in the above-mentioned various reactionprocess formulas can be isolated and purified by usual separation means,such as solvent extraction, solution, recrystallization, columnchloromatography, preparative thin-layer chromatography, etc.

The compounds of the present invention including inevitably theiroptical isomers.

2,3-Dihydro-1H-indene derivatives represented by the general formula caneasily be converted into their acid-addition salts by reacting withpharmaceutically acceptable acids, and the present invention alsoincluding said acid-addition salts. As to the pharmaceuticallyacceptable acids, inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid; organic acids such as acetic acid,oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid,tartaric acid, citric acid, malonic acid, methanesulfonic acid andbenzoic acid can be exemplified and used.

2,3-Dihydro-1H-indene derivatives of the present invention and saltsthereof can be used in any of usual preparations of pharmaceuticalcompositions together with usual pharmaceutically acceptable carriers.Examples of pharmaceutically acceptable carriers which are selecteddepend on the desired form of pharmaceutical compositions includingdiluents and excipients such as fillers, diluents, binders, wettingagents, disintegrating agents, surface active agents and lubricants,etc. No particular restriction is made to the administration unit formsand the pharmaceutical compositions can be selected from any desiredunit form including tablets, pills, powders, liquors, suspensions,granules, capsules, suppositories, injection preparations (includingsolutions, suspensions, etc.), ointments, etc. For the purpose ofshaping in the form of tablets, carriers which are widely used in thisfield can be used, for example excipients such as lactose, sucrose,sodium chloride, glucose, urea, starch, calcium carbonate, kaolin,crystalline cellulose and silicic acid; binding agents such as water,ethanol, propanol, simple sirup, glucose solutions, starch solutions,gelatin solutions, carboxymethyl cellulose, shelac, methyl cellulose,calcium phosphate and polyvinylpyrrlidone; disintegrating agents such asdried starch, sodium alginate, agar-agar powder, laminalia powder,sodium bicarbonate, calcium carbonate, esters of polyoxyethylenesorbitan fatty acids, sodium laurylsulfate, monoglyceride of stearicacid, starch and lactose, etc.; disintegration inhibitors such assucrose, stearine, coconut butter and hydrogenated oils; absorptionaccelerators such as quaternary ammonium bases and sodiumlaurylsulfonate; wetting agents such as glycerin and starch; adsorbingagents such as starch, lactose, kaolin, bentonite and colloidal silicicacid; and lubricants such as purified talc, stearic acid salts, boricacid powder and polyethylene glycols can be exemplified.

If necessary, the tablets can further be coated with usual coatingmaterials to make them into coated tablets, for example tablets coatedwith sugar, tablets coated with gelatin film, tablets coated withenteric coating layers, tablets coated with films or double layertablets as well as multiple layer tablets.

For the purpose of shaping in the form of pills, any carrier which isknown and used widely in this filed can be used, for example, excipientssuch as glucose, lactose, starch, coconut butter, hydrogenated vegetableoils, kaolin, and talc, etc.; binding agents such as powdered arabicgum, powdered tragacnthe gum, geletin and ethanol, etc; disintegratingagents such as laminarial and agar-agar, etc. can be exemplified.

For the purpose of shaping in the form of suppositories, carriers whichare known and widely used in this field can also be used, for examplepolyethylene glycols, coconut butter, higher alcohols, esters of higheralcohols, geletin and semi-synthesized glycerides, etc. can beexemplified.

For the purpose of making in the form of injection preparations,solutions and suspensions prepared are further sterilized and arepreferably isotonic to the blood. In preparing this injectionpreparations in the form of solutions, emulsions and suspensions, anycarrier which is known and is widely used in this field can also beused, for example water, ethanol, prorylene glycol, ethoxylatedisostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylenesorbitan fatty acid esters, etc. In these instances, adequate amounts ofsodium chloride, glucose or glycerin may be added to the desiredinjection preparation to make them isotonic. Furthermore, usualdissolving agents, buffer agents, analgesic agents may be added. Alsocoloring materials, preservatives, perfumes, seasoning agents,sweetening agents and other medicines may be added in the desiredpharmaceutical preparations, if necessary.

For the purpose of making the preparations in the form of pastes, creamsand gels, diluents which are known and used widely in this field canalso be used, for example white petrolatum, paraffin, glycerin,cellulose derivatives, polyethylene glycols, silicons, bentonite, etc.can be exemplified.

The amount of 2,3-dihydro-1H-indene derivatives and their saltsrepresented by the general formula (1) to be contained in pharmaceuticalcompositions is not specifically restricted, and can be suitably beselected from a wide range, and generally 1 to 70% by weight thereof iscontained in the compositions.

Methods for administering the above-mentioned pharmaceuticalcompositions are not specifically restricted, the compositions can beused in various forms of preparations depending upon the age of thepatient, the distinction of sex, the degree of symptoms and otherconditions of the patient, without any restriction. For example,tablets, pills, solutions, suspensions, emulsions, granules and capsulesare administered orally. Injection preparations are administeredintraveneously singly, or administered with usual injectabletransfusions such as glucose solutions, amino acids solutions, etc.; andfurther, if necessary, the injection preparations are administeredsingly intramuscularly, intracutaneously, subcutaneously orintraperitoneally. Suppositories are administered into rectum.

The dosage of the above-mentioned pharmaceutical preparations can beselected suitable according to the methods for administrations, the ageof the patient, the distinction of sex and other conditions as well asthe degree of the symptoms, and generally pharmaceutical compositionscontaining 0.2 to 200 mg per kg of the body weight per day of the2,3-dihydro-1H-indene derivative or its acid-addition salt representedby the general formula (1) may be used.

The present invention is now illustrated by referring to the followingexamples in which the preparations of the starting materials areexplained in Reference Examples, further the preparations of theobjective 2,3-dihydro-1H-indene derivatives are explained in Examples.However, the present invention is not restricted only to these examples.

Reference Example 1

A mixture of 196 g of 2,3-dihydro-7-hydroxy-4-methyl-1H-inden-1-one, 80g of potassium hydroxide and 2.5 liters of methanol was refluxed for 30minutes. Then the reaction mixture was cooled to room temperature, then250 g of cinnamyl bromide was added dropwise to the reaction mixtureunder vigorous stirring condition. The reaction mixture was furtherstirred for 8 hours at the same temperature, then the crystals separatedtherein were collected by filtration, washed with cold methanol anddried. Recrystallized from ethanol to yield 126 g of7-cinammyloxy-2,3-dihydro-4-methyl-1H-inden-1-one. Colorless needle-likecrystals. Melting point: 110°-111° C.

Reference Example 2

A mixture of 7 g of 7-cinammyloxy-2,3-dihydro-4-methyl-1H-inden-1-oneand 40 ml of tetrahydronaphthalene was refluxed for 3 hours undernitrogen gas stream. After the reaction was completed, the reactionmixture was cooled to room temperature, then was purified by a silicagel column chromatography (eluent: n-hexane:ethyl acetate=10:1).Recrystallized from ethanol to yield 2.64 g of2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one.Colorless flake-like crystals. Melting point: 131°-131.5° C.

Reference Example 3

16.2 Grams of 7-hydroxy-4,6-dimethyl-1-indane oxime was dissolved in 200ml of acetic acid, then 1.0 g of platinum oxide catalyst was addedthereto, and the whole mixture as catalytically reduced under 5atmospheric hydrogen gas pressure at room temperature for 8 hours. Afterthe reaction was completed, the catalyst was removed by filtration, thenthe filtrate was concentrated to dryness under a reduced pressure. Theresidue thus obtained was dissolved in 200 ml of ethanol, then hydrogenchloride gas was saturated in this solution by blowing. The solution wasconcentrated to dryness by removing the solvent under a reduced pressureto yield 3.40 g of 1-amino-2,3-dihydro-7-hydroxy-4,6-dimethyl-1H-indenehydrochloride in the form of colorless needle-like crystals. Meltingpoint: 229°-230° C. (Decomposed)

Reference Examples 4-5

By a method similar to that described in reference Examples 3, and byusing suitable starting materials, there were prepared compounds asfollows.

    ______________________________________                                        Reference                                                                     Example                                                                       No.        Name of Compound                                                   ______________________________________                                        4          1-Amino-2,3-dihydro-7-hydroxy-4-methyl-6-                                     sec-butyl-1H-indene hydrochloride                                             Colorless powdery crystals (Recrystal-                                        lized from methanol-diethyl ether)                                            Melting point: 177.5-179° C.                                5          1-Amino-2,3-dihydro-7-hydroxy-2,2,4,6-                                        tetramethyl-1H-indene hydrochloride                                           Colorless needle-like crystals (Recrystal-                                    lized from ethanol)                                                           Melting point: 231-233° C.                                  ______________________________________                                    

Reference Example 6

A solution containing 17.7 g of1-amino-4,6-dimethyl-7-hydroxy-2,3-dihydro-1H-indene and 15.2 g oftriethylamine in 200 ml of chloroform was ice-cooled under stirringcondition, then 13.56 g of chloroacetyl chloride was added dropwisethereto. After the dropwise addition was finished, the reaction mixturewas stirred at 25° C. for 3 hours. After the reaction was completed, thereaction mixture was washed with 100 ml of 1N-hydrochloric acid aqueoussolution, further washed three times with 100 ml of water, then driedwith anhydrous magnesium sulfate, and the solvent was removed byevaporation under a reduced pressure. Recrystallized from ethanol toobtain 21 g of1-chloroacetylamino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene.Colorless needle-like crystals. Melting point: 131°-132° C.

Reference Examples 7-9

By a method similar to that described in Reference Example 6, and byusing suitable starting materials, there were prepared compounds ofReference Examples 7-9 shown in Table 1 as follows.

                                      TABLE 1                                     __________________________________________________________________________     ##STR31##                                                                                                 Crystal form                                     Reference                    (Recrystallization                                                                      Melting point                          Example No.                                                                          R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                          R.sup.4                                                                             R.sup.8                                                                              solvent)  (°C.)                           __________________________________________________________________________    7      CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            COCH.sub.2 Cl                                                                        Colorless 200-201                                                             needle-like crystals                                                          (Ethanol)                                        8      H  H  CH.sub.3                                                                          ##STR32##                                                                          COCH.sub.2 Cl                                                                        Colorless needle-like crystals (Ethanol)                                                111.5-114.5                            9      CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR33##                                                                          COCH.sub.2 Cl                                                                        Colorless needle-like crystals (Ethanol)                                                158-160                                __________________________________________________________________________

Reference Example 10

2.00 Grams of (3-methoxyphenyl)piperazine was dissolved in 20 ml ofchloroform, then 1.40 ml of triethylamine was added to this solution,further 0.92 ml of chloroacetyl chloride was added dropwise graduallythereto at 0° C., after the dropwise addition was finished, the reactionmixture was further stirred at the same temperature for 30 minutes.After the reaction was completed, the reaction mixture was washed withwater, and was dried with anhydrous magnesium sulfate. The solvent wasremoved by evaporation to obtain 3.2 g of1-chloroacetyl-4-(3-methoxyphenyl)piperazine in the form of an oilysubstance.

Reference Example 11

To a mixture of 1.50 g of 4-(3-chlorophenyl)-piperazine and 0.31 g ofsodium hydride was added 2.4 ml of epichlorohydrin and the reactionmixture as stirred at room temperature for 30 minutes. After thereaction was completed, the reaction mixture was extracted with 100 mlof ethyl acetate, and the extract was washed 5 times with 100 ml ofwater, then dried with anhydrous magnesium sulfate. The solvent wasremoved by evaporation to obtain the residue which was purified by meansof a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 1.66 g of4-(3-chlorophenyl)-1-(2,3-epoxypropyl)piperazine as in the form of anoily substance.

Reference Example 12

10 Grams of 2,4-dimethylphenyl cinnamate was melted at 80° C., thenunder stirring condition, 7.93 g of finely pulverized aluminium chloridewas added thereto, and stirred at the same temperature for 10 minutes.100 Grams of ice was added to the reaction mixture and extracted with200 ml of methylene chloride. The extract was washed with water, driedthen concentrated under a reduced pressure. The residue thus obtainedwas purified by means of a silica gel column chromatography(eluent:chloroform:n-hexane=1:1), then the purified product wasrecrystallized from ethanol to obtain 2.89 g of2,3-dihydro-7-hydroxy-3-phenyl-1H-inden-1-one. Light yellow powderycrystals. Melting point: 137°-138° C.

Reference Example 13

212.6 Grams of 4,6-dimethyl-2-(2-phenylacetyl)-phenol was dissolved in350 ml of N,N,N',N'-tetramethyldiaminomethane, then under ice-cooledcondition with stirring, 350 ml of acetic anhydride was added dropwisethereto. The reaction mixture was further stirred at room temperaturefor 2 hours, then was poured in 1 kg of ice and stirred vigorously. Thecrystals separated in the mixture were collected by filtration, washeswith water, then dried. Recrystallized from ethanol to obtain 186 g of2,4-dimethyl-6-(2-phenylacryloyl)phenol. Colorless needle-like crystals.Melting point: 83°-84° C.

Reference Example 14

Into 15 ml of concentrated sulfuric acid, under ice-cooled conditionwith stirring, 3.0 g of 2,4-dimethyl-6-(2-phenylacryloyl)phenol wasadded gradually, then the whole mixture was stirred at room temperaturefor 1 hour. The reaction mixture was poured in 100 g of ice andextracted with 200 ml of methylene chloride. The extract was washed withwater and dried with anhydrous magnesium sulfate, then was concentratedunder a reduced pressure to obtain the residue. The residue wasrecrystallized from ethanol to obtain 2.11 g of2,3-dihydro-4,6-dimethyl-2-phenyl-7-hydroxy-1H-inden-1-one.

Colorless prism-like crystals. Melting point: 90.5°-91° C.

NMR (CDCl₃) δ: 9.03 (s, 1H), 7.42-7.08 (m, 6H),

3.92 (d-d, 1H, J=8.4 Hz, 3.6 Hz), 3.52 (d-d,

1H, J=16.8 Hz, 8.4 Hz), 3.02 (d-d, 1H, J=16.8 Hz,

3.6 Hz), 2.23 (s, 6H)

Reference Examples 15-20

By a method similar to that described in Reference Example 14, by usinga suitable starting material, there were prepared compounds of ReferenceExamples 15-20 as shown in Table 2 as follows.

                                      TABLE 2                                     __________________________________________________________________________     ##STR34##                                                                    Reference                          Crystal form                               Example                            (Recrystalliza-                                                                         Melting                          No.   R.sup.1  R.sup.2                                                                          R.sup.3                                                                          R.sup.4   R.sup.6                                                                         R.sup.7                                                                         tion solvent)                                                                           point (°C.)               __________________________________________________________________________    15                                                                                   ##STR35##                                                                             H  CH.sub.3                                                                         CH.sub.3  H H Light brown needle-like crystals                                              (Ethanol-water)                                                                         118-120                          16                                                                                   ##STR36##                                                                             H  CH.sub.3                                                                         CH.sub.3  H H Colorless Powdery crystals (Ethanol)                                                    89-90                            17                                                                                   ##STR37##                                                                             H  CH.sub.3                                                                         CH.sub.3  H H Light brown powdery crystals (Ethanol)                                                  92-93                            18    CH.sub.3 CH.sub.3                                                                         CH.sub. 3                                                                         ##STR38##                                                                              H H Colorless needle-like crystals                                                (Ethanol) 192-193                          19                                                                                   ##STR39##                                                                             CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3  H H Light yellow granular crystals                                                (Ethanol) 93-94                            20                                                                                   ##STR40##                                                                             H  Cl CH.sub.3  H H Colorless powdery crystals (Ethanol)                                                    107-109                          __________________________________________________________________________

Reference Example 21

To a mixture of 140 g of 2'-methoxy-5'-methylpropiophenone, 83.4 g ofbenzaldehyde and 1.5 liters of ethanol was added 154 ml of 20%-sodiumhydroxide aqueous solution under stirring. The reaction mixture wasstirred overnight at room temperature, then 10%-hydrochloric acid wasadded to make the reaction mixture acidic, and extracted with benzene.The benzene extract was washed with water and an aqueous solutionsaturated with sodium chloride in this order, then dried to obtain 212 gof 2'-methoxy-5'-methyl-2-benzylidenepropiophenone. Yellow oilysubstance.

NMR (CDCl₃) δ: 2.20 (s, 3H), 2.30 (s, 3H), 3.73 (s, 3H),

6.81 (d, 2H, J=7 Hz), 7.00-7.60 (m, 8H)

Reference Example 22

To 210 g of 2'-methoxy-5'-methyl-2-benzylidenepropiophneone was added 1kg of trifluoroacetic acid, and the mixture was refluxed for 10 hoursunder stirring condition. After the reaction was completed, the reactionmixture was concentrated and extracted with methylene chloride. Theextract was washed with an aqueous solution saturated with sodiumbicarbonate, water and an aqueous solution saturated with sodiumchloride in this order, then dried and concentrated. Recrystallized frombenzene to obtain 40 g of2,3-dihydro-2,4-dimethyl-3-phenyl-7-methoxy-1H-inden-1-one as in theform of a mixture of cis-form and trans-form of 2- and 3-positions inthe indene skeleton (hereinafter referred to as cis-trans mixture).

cis-Isomer: NMR (CDCl₃) δ: 0.81 (d, J=7 Hz, 3H),

1.95 (s, 3H), 300 (d, q, 1H, J=7 Hz), 3.95 (s,

3H), 4.57 (d, 1H, J=7 Hz), 6.70-7.47 (m, 7H)

trans-Isomer: NMR (CDCl₃) δ: 1.34 (d, J=7 Hz, 3H),

1.84 (s, 3H), 2.50 (d, q, 1H, J=4 Hz, J-7 Hz),

3.90-4.07 (m, 4H), 6.70-7.47 (m, 7H).

Reference Example 23

A solution of 19.6 g of2,3-dihydro-2,4-dimethyl-3-phenyl-7-methoxy-1H-inden-1-one, 11.5 g ofsodium iodide and 10.3 of aluminium chloride in 200 ml of acetonitrilewas stirred at room temperature for 2 hours. After the reaction wascompleted, the reaction mixture was poured in water, and was extractedwith dichloromethane. The extract was once filtered through Celite (atrademark for diatomaceous earth, manufactured by Jhns-Manville ProductsCorp., Celite Division, Manville, N.J., U.S.A.) and washed with anaqueous solution of sodium bicarbonate and with an aqueous solutionsaturated with sodium chloride. After dried the extract, it wasconcentrated and the residue obtained was purified by means of a silicagel column chromatography. Recrystallized from n-hexane to obtain 11.4 gof cis-trans mixture of2,3-dihydro-2,4-dimethyl-3-phenyl-7-hydroxy-1H-inden-1-one. Colorlessprism-like crystals.

cis-Isomer: NMR (CDCl₃) δ: 0.81 (d, 3H, J=7 Hz), 1.89

(s, 3H), 3.08 (d, q, 1H, J=7 Hz), 4.61 (d, 1H,

J=7 Hz), 6.57-7.47 (m, 7H), 8.94 (s, 1H).

trans-Isomer: NMR (CDCl₃) δ: 1.37 (d, 3H, J=7 Hz), 1.80 (s, 3H), 2.58(d, q, J=4 Hz, 7 Hz), 3.98 (d, J=7 Hz, 1H), 6.57-7.47 (m, 7H), 9.04 (s,1H).

Reference Example 24

A solution of 19.0 g of2,3-dihydro-2,4-dimethyl-3-phenyl-7-hydroxy-1H-inden-1-one, 13.98 ofcrotyl bromide and 5.47 g of potassium hydroxide in 200 ml of acetonewas heated and refluxed under stirring condition. After the reaction wascompleted, the reaction mixture was concentrated and extracted withethyl acetate, then the extract was washed with water and with anaqueous solution saturated with sodium chloride, then dried. The extractwas concentrated by removing the solvent under a reduced pressure, thenrecrystallized from methanol to obtain 11.8 g of2,3-dihydro-2,4-dimethyl-3-phenyl-7-crotyloxy-1H-inden-1-one as in theform of cis-trans mixture. Colorless stick-like crystals. Melting point:138.5°-139.5° C.

cis-Isomer: NMR (CDCl₃) δ: 0.78 (d, 3H, J=7 Hz),

1.66-1.78 (m, 3H), 1.93 (s, 3H), 2.98 (d, q,

1H, J=7 Hz), 4.70-4.83 (m, 2H), 5.56-6.20

(m, 2H), 6.67-7.43 (m, 7H)

trans-Isomer: NMR (CDCl₃) δ: 1.67 (d, 3H, J=7 Hz),

1.66-1.78 (m, 3H), 1.82 (s, 3H), 2.48 (d, q,

1H, J=4 Hz, 7 Hz), 4.53-4.67 (m, 2H), 5.56-6.20

(m, 2H), 6.67-7.43 (m, 7H).

Reference Example 25

11 Grams of2,3-dihydro-2,4-dimethyl-3-phenyl-4-methyl-7-crotyloxy-1H-inden-1-onewas added to 55 ml of tetrahydronaphthalene and the mixture was heatedand refluxed for 6 hours with stirring condition. After the reaction wascompleted, the reaction mixture was concentrated by removal of thesolvent, and the residue thus obtained was purified by means of a silicagel column chromatography. 11.2 Grams of 2,3-dihydro-2,4-dimethyl-3-phenyl-6-(1-buten-3-yl)-7-hydroxy-1H-inden-1-one wasobtained as cis-trans mixture. Yellow oily substance.

cis-Isomer: NMR (CDCl₃) δ: 0.80 (d, 3H, J=7 Hz), 1.36

(d, 3H, J=8 Hz), 1.87 (s, 3H), 3.10 (d, q, 1H,

J=7 Hz), 3.70-4.06 (m, 1H), 4.57 (d, 1H,

J=7 Hz), 4.93-5.23 (m, 2H), 5.80-6.26 (m, 1H),

6.66-7.43 (m, 6H), 9.23 (s, 1H).

trans-Isomer NMR (CDCl₃) δ: 1.34 (d, 3H, J=7 Hz), 1.36

(d, 3H, J=8 Hz), 1.80 (s, 3H), 2.58 (d, q, 1H,

J=4 Hz, 7 Hz), 3.94 (d, 1H, J=4 Hz), 3.70-4.06

(m, 1H), 4.93-5.23 (m, 2H), 5.80-6.26 (m, 1H),

6.66-7.43 (m, 6H), 9.33 (s, 1H).

Reference Example 26

10 Grams of 2,3-dihydro-4,6dimethyl-7-hydroxy-1H-inden-1-one wasdissolved in 200 ml of dimethylformamide, then 5.45 g of 60%-sodiumhydride was added gradually thereto and the reaction mixture was stirredat room temperature for 30 minutes. Next, 6.91 ml of p-anisaldehyde wasadded to the reaction mixture and further stirred at room temperaturefor 1 hour. The reaction mixture was poured into 500 ml of ice-water,then acidified by adding hydrochloric acid, and the crystals formed werecollected by filtration. The crystals were washed with water and withn-hexane and dried. Recrystallized from ethanol to obtain 16.09 g of2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one.Yellow needle-like crystals. Melting point: 192°-193° C.

Reference Example 27

16.09 Grams of2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-onewas dissolved in a mixed solvent of 150 ml of ethylacetate with 100 mlof acetic acid, this solution was let subjected to catalytic reductionat room temperature under 3 atmospheric hydrogen gas pressure in thepresence of 1.5 g of palladium black as the hydrogenation catalyst.After the catalytic reduction, the catalyst was removed by filtration,and the filtrate was concentrated by removing the solvent under reducedpressure. The residue thus obtained was purified by a silica gel columnchromatography (eluent: n-hexane: ethyl acetate=9:1) to obtain 8.5 g of2,3-dihydro-4, 6-dimethyl-7-hydroxy-2-(4-methoxybenzyl)-1H-inden-1-oneas in the form of colorless oily substance.

NMR (CDCl₃) δ: 2.12 (s, 3H), 2.18 (s, 3H), 2.40-3.40

(m, 5H), 3.76 (s, 3H) 6.81 (d, 2H, J=8 Hz), 7.09

(s, 1H), 7.11 (d, 2H, J=8 Hz), 9.03 (s, 1H).

Reference Examples 28-30

By a method similar to that described in Reference Example 27 and byusing suitable starting material, there were prepared compounds ofReferences Examples 28-30 as follows.

    ______________________________________                                        Reference                                                                     Example                                                                       No.        Name of compound                                                   ______________________________________                                        28         2,3-Dihydro-4,6-dimethyl-y-hydroxy-2-                                         benzyl-1H-inden-1-one                                                         Colorless prism-like crystals (from ethanol)                                  Melting point: 107-108° C.                                             NMR (CDCl.sub.3) δ: 2.11(s, 3H), 2.19(s, 3H),                           2.40-3.50(m, 5H), 7.13(s, 1H), 7.25(m, 5H),                                   9.04(s, 1H).                                                       29         2,3-Dihydro-4,6-dimethyl-7-hydroxy-2-(4-                                      chlorobenzyl)-1H-inden-1-one                                                  Colorless prism-like crystals (from  -n-                                      hexane)                                                                       Melting point: 108-109° C.                                             NMR (CDCl.sub.3) δ: 2.12(s, 3H), 2.19(s, 3H),                           2.20-3.40(m, 5H), 7.09(s, 1H), 7.10-7.40(m,                                   4H), 8.70-9.30(broad, s, 1H).                                      30         2,3-Dihydro-4,6-dimethyl-7-hydroxy-2-(3,4-                                    methylenedioxybenzyl)-1H-inden-1-one                                          Colorless prism-like crystals (from ethanol)                                  Melting point: 108-109° C.                                             NMR (CDCl.sub.3) δ: 2.17(s, 3H), 2.21(s, 3H),                           2.40-3.40(m, 5H), 5.90(s, 2H), 6.71(m, 3H),                                   7.13(s, 1H), 9.04(s, 1H).                                          ______________________________________                                    

Reference Examples 31-33

By a method similar to that described in Reference Example 26, by usingsuitable starting materials, there were prepared compounds of ReferenceExamples 31-33 as follows.

    ______________________________________                                        Reference                                                                     Example                                                                       No.        Name of compound                                                   ______________________________________                                        31         2,3-Dihydro-4,6-dimethyl-7-hydroxy-2-                                         benzylidene-1H-inden-1-one                                                    Light yellow prism-like crystals (from                                        ethanol)                                                                      Melting point: 161-162° C.                                             NMR (CDCl.sub.3) δ: 2.18(s, 3H), 2.22(s, 3H),                           3.71(sm 2H), 7.08(s, 1H), 7.30-7.70(m, 5H), 9.23                              (s, 1H).                                                           32         2,3-Dihydro-4,6-dimethyl-7-hydroxy-2-(4-                                      chlorobenzylidene)-1H-inden-1-one                                             Light yellow needle-like crystals (from                                       ethanol)                                                                      Melting point: 184-185° C.                                             NMR (CDCl.sub.3) δ: 2.19(s, 3H), 2.23(s, 3H),                           3.69(s, 2H), 7.10(s, 1H), 7.30-7.60(m, 4H),                                   9.20(s, 1H).                                                       33         2,3-Dihydro-4,6-dimethyl-7-hydroxy-2-(3,4-                                    methylenedioxybenzylidene)-1H-inden-1-one                                     Light yellow needle-like crystals (from                                       ethanol)                                                                      Melting point: 243-244° C.                                             NMR (DMSO-d.sub.6) δ: 2.18(s, 3H), 2.30(s,                              3H), 3.90(s, 2H), 6.10(s, 2H), 7.02(d,                                        J=9Hz, 1H), 7.25(s, 1H), 7.28(d, 1H, J=2Hz),                                  7.36(d-d, 1H, J=9Hz, 2Hz).                                         ______________________________________                                    

Reference Example 34

28.3 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-benzyl-1H-inden-1-onewas dissolved in 350 ml of dimethylformamide, then 5.2 g of 60%-sodiumhydride was added thereto at 55°-60° C. and the mixture was stirred for40 minutes. Next 8 ml of methyl iodide was added thereto, and the wholemixture was heated to the same temperature for 1 hour. Followed by 5.2 gof 60%-sodium hydride was added and stirred for 40 minutes at the sametemperature. Next, 8 ml of methyl iodide was further added and heatedfor 10 minutes at the same temperature. Furthermore, 5.2 g of 60%-sodiumhydride was added to the reaction mixture and stirred for 55 minutes atthe same temperature, and 8 ml of methyl iodide was added to thereaction mixture and heated to the same temperature for 3 hours and 20minutes. After the reaction was completed, dimethylformamide was removedunder a reduced pressure and the residue obtained was extracted withethyl acetate. The extract was washed with water and with an aqueoussolution saturated with sodium chloride in this order, then the solventwas removed under a reduced pressure to obtain the residue. The residuewas purified by means of a silica gel column chromatography (eluent:n-hexane; ethyl acetate) to obtain 23.0 g of2,3-dihydro-2,4,6-trimethyl-7 -methoxy-2-benzyl-1H-inden-1-one.

NMR (CDCl₃) δ: 1.25 (s, 3H), 2.14 (s, 3H), 2.21 (s,

3H), 2.30-3.20 (m, 4H), 3.91 (s, 3H), 7.15

(m, 5H), 7.23 (s, 1H).

Reference Example 35

23.0 Grams of2,3-dihydro-2,4,6-trimethyl-7-methoxy-2-benzyl-1H-inden-1-one and 25.8 gof sodium iodide were dissolved in 90 ml of acetonitrile. To thissolution was added 22.9 g of aluminium chloride at room temperature andstirred for 1 hour. Then the solvent was removed by evaporation under areduced pressure, and the residue thus obtained was extracted with ethylacetate. The extract was washed with an aqueous solution saturated withsodium chloride, an aqueous solution of sodium thiosulfate and anaqueous solution saturated with sodium chloride in this order, and theinsoluble matters were removed by filtration. The solvent was removed byevaporation and the residue thus obtained was recrystallized fromn-hexane to obtain 19.7 of2,3-dihydro-2,4,6-trimethyl-7-hydroxy-2-benzyl-1H-indene-1-one.Colorless prism-like crystals.

Melting point: 86°-87° C.

NMR (CDCl₃) δ: 1.22 (s, 3H), 2.08 (s, 3H), 2.15 (s, 3H),

2.30-3.20 (m, 4H), 7.02 (s, 1H), 7.08-7.40

(m, 5H), 9.03 (s, 1H).

Reference Example 36

5.0 Grams of 4,6-dimethyl-7-hydroxy-2-phenyl-1-indanone was dissolved in10 ml of diethyl ether and 10 ml of dichloromethane, then this solutionwas added dropwise gradually to a mixture of a solution of 2.55 ml ofbenzylamine in 10 ml of diethyl ether with 8 g of Molecular sieves 5A.The whole mixture was stirred at room temperature for 2 days andfiltered by using Celite to obtain filtrate. The Celite used was washedwith dichloromethane and ethanol, then these washing liquors werecombined with the above-mentioned filtrate and concentrated.Recrystallized from dichloromethane-ethanol to obtain 3.83 g of4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene. Orangeneedle-like crystals.

Melting point: 214°-215° C.

Example 1

An ethanol solution containing 120 g of2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one,45 of hydroxylamine hydrochloride and 200 ml of pyridine in 1,200 ml ofethanol was refluxed for 4 hours. After the reaction was completed, thereaction mixture was concentrated to dryness under a reduced pressure,then the residue thus obtained was dissolved in 2 liters of ethylacetate and washed three times with 1 liter of water each time, and theresidue was dried again under a reduced pressure. Recrystallized fromethyl acetate/n-hexane mixture to obtain 90 g of2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-oneoxime. Light yellow flake-like crystals. Melting point: 146° C.(Decomposed).

Examples 2-21

By a method similar to that described in Example 1, and by using asuitable starting material, there were prepared compounds of Examples2-21 shown in Table 3 as follows.

                                      TABLE 3                                     __________________________________________________________________________     ##STR41##                                                                                                                  Crystal form                    Example                                       (Recrystallization                                                                      Melting               No.  R.sup.1       R.sup.2                                                                          R.sup.3                                                                          R.sup.4       R.sup.6                                                                              solvent)  point                 __________________________________________________________________________                                                            (°C.)           2   H             H  CH.sub.3                                                                          ##STR42##    H      Colorless flake- like                                                         crystals (Water)                                                                        279 (decomposed)       3   H             H  CH.sub.3                                                                          ##STR43##    H      Colorless powdery crystals                                                    (Ethanol- diethyl                                                                       187.5-189.5            4                                                                                  ##STR44##    H  CH.sub.3                                                                         CH.sub.3      H      Orange granular crystals                                                      (Ethanol) 190-191 (decompose                                                            d)                     5                                                                                  ##STR45##    H  CH.sub.3                                                                         CH.sub.3      H      Colorless prism- like                                                         crystals (Ethanol)                                                                      173-175                6   H             H  CH.sub.3                                                                         CH.sub.3                                                                                     ##STR46##                                                                           Colorless powdery crystals                                                    (Ethanol) 156.5-158              7   CH.sub.3      H  CH.sub.3                                                                          ##STR47##                                                                                   ##STR48##                                                                           Colorless flake- like                                                         crystals ( -n-Hexane)                                                                   121.5-124              8                                                                                  ##STR49##    H  CH.sub.3                                                                         CH.sub.3      H      Light yellow needle-like                                                      crystals (Ethanol-water)                                                                156-158                9                                                                                  ##STR50##    H  CH.sub.3                                                                         CH.sub.3      H      Light yellow needle-like                                                      crystals (Ethanol-water)                                                                175-177               10                                                                                  ##STR51##    H  CH.sub.3                                                                         CH.sub.3      H      Colorless powdery crystals                                                    (Ethanol-water)                                                                         182-183               11   CH.sub.3      CH.sub.3                                                                         CH.sub.3                                                                          ##STR52##    H      Yellow needle- like                                                           crystals (Methanol)                                                                     246-248               12                                                                                  ##STR53##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      H      Colorless granular crystals                                                   (Ethanol) 181-183               13                                                                                  ##STR54##    H  CH.sub.3                                                                         CH.sub.3      H      Yellow prism-like crystals                                                    (Ethanol) 152-153               14                                                                                  ##STR55##    H  Cl CH.sub.3      H      Light yellow powdery                                                          crystals (Ethanol)                                                                      169-171               15                                                                                  ##STR56##    H  CH.sub.3                                                                         Br            H      Colorless powdery crystals                                                    (Ethanol) 162-165 (decompose                                                            d)                    16                                                                                  ##STR57##    H  CH.sub.3                                                                         CH.sub.3      H      Colorless prism- like                                                         crystals (Ethanol)                                                                      163-168               17                                                                                  ##STR58##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      H      Colorless powdery crystals                                                    (Ethanol) 161-162               18                                                                                  ##STR59##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      H      Colorless prism- like                                                         crystals (Ethanol)                                                                      164-165               19                                                                                  ##STR60##    H  CH.sub.3                                                                         CH.sub. 3     H      Colorless prism- like                                                         crystals (Ethanol)                                                                      164-165               20                                                                                  ##STR61##    H  CH.sub.3                                                                         CH.sub.3      H      Colorless prism- like                                                         crystals (Ethanol- -n-hexane                                                  )         170-171               21                                                                                  ##STR62##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      H      Colorless prism- like                                                         crystals ( -n-Hexane)                                                                   109-110               __________________________________________________________________________

Example 22

2.93 Grams of2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-oneoxime and 0.293 g of platinum oxide were suspended in 200 ml of aceticacid, then the suspension was reduced at room temperature under 3atmospheric hydrogen pressure for 8 hours. After the completion ofhydrogenation, the catalyst was removed by filtration, and the filtratethus obtain was concentrated by dryness under a reduced pressure. Theresidue thus obtained was dissolved in 100 ml of ethanol and the pH ofthe solution was adjusted to about pH=1 by adding an ethanol solutionwas again concentrated to dryness under a reduced pressure. The residuethus obtained was recrystallized from ethanoldiethyl ether to obtain0.88 g of1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenylpropyl)-1H-indenehydrochloride. Colorless powdery crystals. Melting point: 187.5°-189.5°C.

Example 23

2.93 Grams of2,3-dihydro-y-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1-H-inden-1-oneoxime and 0.293 g of platinum oxide were suspended in 200 ml of aceticacid, then the suspension was reduced at room temperature under 7atmospheric hydrogen pressure for 8 hours. After the completion of thehydrogenation, the catalyst was removed by filtration, and the filtratethus obtained was concentrated to dryness under a reduced pressure. Theresidue thus obtained was dissolved in 100 ml of ethanol, and the pH ofthis solution was adjusted to about pH=1 by adding an ethanol solutionsaturated with hydrogen chloride gas, then this solution was againconcentrated to dryness under a reduced pressure. The residue thusobtained was recrystallized from diethyl ether-n-hexane to obtain 1.0 gof1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-cyclohexylpropyl)-1H-indenehydrochloride. Colorless powdery crystals. Melting point: 184°-185.5° C.

Example 24

4.79 Grams of 2,3-dihydro-4,6-dimethyl-2-phenyl-7-hydroxy-1H-inden-1-onewas dissolved in 88 ml of glacial acetic acid, and this solution wassubjected to catalytic hydrogenation in the presence of 0.71 g ofplatinum oxide, at 50° C., under 4 atmospheric hydrogen gas pressure for18 hours. After the completion of the hydrogenation, the catalyst wasremoved by filtration and the filtrate was concentrated under a reducedpressure. To the residue thus obtained was added 100 ml of water,neutralized with an aqueous solution saturated with sodium bicarbonate,then extracted with 300 ml of chloroform. The insoluble matters werecollected by filtration, and washed with water and diethyl ether, thenrecrystallized from ethanol to obtain 2.50 g of1-amino-2-cyclohexyl-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indeneacetate (in which the substituents bonded at 1- and 2-positions in theindene skeleton are oriented as trans-form). Light yellow powderycrystals.

Melting point: 170°-172° C. (Decomposed)

NMR (DMSO-d₆) δ: 6.74 (s, 1H), 447 (d, 1H, J=6 Hz),

2.80-2.45 (m, 2H), 2.09 (s, 6H), 1.85 (s, 3H),

1.97-0.83 (m, 12H).

The filtrate obtained after removal of the insoluble matters was washedwith water and dried with anhydrous magnesium sulfate. The solvent wasremoved by evaporation under a reduced pressure to obtain the residue.Recrystallized from ethanol to obtain 1.40 g of 1-amino-2-cyclohexyl-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene (in which the substituentsbonded at 1- and 2-positions in the indene skeleton are oriented ascis-form). Colorless needle-like crystals. Melting point: 125°-126° C.

NMR (CDCl₃) δ: 677 (s, 1H), 4.30 (d, 1H, J=7.5 Hz),

3.03-2.70 (m, 1HO, 2.87 (d-d, 1H, J=15 Hz,

7.5 Hz), 2.42 (d-d, 1H, J=15 Hz, 3Hz), 2.18 (s,

3H), 2.12 (s, 3H), 1.07-1.97 (m, 11H).

Example 25

3.00 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-inden-1-oneoxime was dissolved in 55 ml of glacial acetic acid, and this solutionwas subjected to catalytic hydrogenation in the presence of 0.3 g ofplatinum oxide at room temperature under 4 atmospheric hydrogen gaspressure. The hydrogenation was terminated at the point when thestoichiometric amount of hydrogen was absorbed. The catalyst was removedby filtration and the filtrate thus obtained was concentrated. Theresidue thus obtained was dissolved in water and the pH of this solutionwas adjusted to about pH 8 by adding an aqueous solution of sodiumbicarbonate, then extracted with 200 ml of chloroform. The chloroformextract was washed with water, dried with anhydrous magnesium sulfate,then concentrated under a reduced pressure. Recrystallized from ethanolto obtain 0.24 g of1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-indene Colorlessneedlelike crystals. Melting point: 135°-136° C.

NMR (CDCl₃) δ: 7.30-7.13 (m, 3H), 7.03-6.87 (m,

2H), 6.80 (s, 1H), 4.89 (d, 1H, J=7.5 Hz), 3.68

(d-d-d, 1H, J=7.5 Hz, 7.5 Hz, 3.0 Hz), 3.25 (d-d,

1H, J=16.5 Hz, 7.5 Hz), 2.95 (d-d, 1H, J=16.5,

3.0 Hz), 2.18 (s, 6H).

Examples 26-44

By methods similar to those described in Examples 22-25, and by usingsuitable starting materials, there were prepared compounds of Examples26-44 shown in Table 4 as follows.

                                      TABLE 4                                     __________________________________________________________________________     ##STR63##                                                                                                             Crystal form                                                                           Melting                     Example                                  (Recrystalli-                                                                          point                       No.  R.sup.1       R.sup.2                                                                          R.sup.3                                                                          R.sup.4                                                                             R.sup.6                                                                              R.sup.7                                                                          zation solvent)                                                                        (°C.)                                                                        Salt                  __________________________________________________________________________    26                                                                                  ##STR64##    CH.sub.3                                                                         CH.sub.3                                                                         H     H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              206-208 (NMR                                                                        Hydro- chloride       27                                                                                  ##STR65##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Light yellow needle-like                                                      crystals (Ethanol)                                                                     124-126 (NMR                                                                        Acetate               28                                                                                  ##STR66##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Light yellow  needle-like                                                     crystals (Ethanol)                                                                     131.5-132.5 (NMR                                                                    --)                   29   H             H  CH.sub.3                                                                         CH.sub.3                                                                             ##STR67##                                                                           H  Colorless powdery crystals                                                    (Ethanol)                                                                              212-214 (decomposed)                                                          (NMR *10)                                                                           --                    30   CH.sub.3      H  CH.sub.3                                                                          ##STR68##                                                                           ##STR69##                                                                           H  Colorless powdery crystals                                                    (Diethyl ether)                                                                        128-129                                                                             Acetate               31                                                                                  ##STR70##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    (Ethanol- diethyl                                                                      134-138 (NMR                                                                        Semi- fumarate        32                                                                                  ##STR71##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    crystals (Ethanol- ethyl                                                      acetate) 198 (NMR                                                                            Hydro- chloride       33                                                                                  ##STR72##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              194-197 (NMR                                                                        Fumarate              34                                                                                  ##STR73##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless prism-like crystals                                                 (Ethanol)                                                                              193-194 (NMR                                                                        Semi- fumarate        35                                                                                  ##STR74##    H  CH.sub.3                                                                         Br    H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              123-124 (NMR                                                                        --3)                  36                                                                                  ##STR75##    H  Cl CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              113-115 (NMR                                                                        --)                   37                                                                                  ##STR76##    H  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                     H      H  Colorless prism-like crystals                                                 (Ethanol)                                                                               79-80 (NMR                                                                         --)                   38                                                                                  ##STR77##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              145-146 (NMR                                                                        Semi- fumarate                                                                mono- hydrate         39                                                                                  ##STR78##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless needle-like crystals                                                (Ethanol)                                                                              215-216 (NMR                                                                        Fumarate              40                                                                                  ##STR79##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless powdery crystals                                                    (Ethanol)                                                                              184-185 (NMR                                                                        Semi- fumarate        41                                                                                  ##STR80##    H  CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless needle-like crystals                                                (Ethanol)                                                                              196-197 (NMR                                                                        Hydro- chloride       42                                                                                  ##STR81##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            H      CH.sub.3                                                                         Colorless needle-like crystals                                                (Ethanol)                                                                              247-249 (decomposed)                                                                Hydro- chloride.1/                                                            4 hydrate             43                                                                                  ##STR82##    H  CH.sub.3                                                                         H     H      H  Colorless granular crystals                                                   (Ethanol)                                                                              192-196 (NMR                                                                        Hydro- chloride       44                                                                                  ##STR83##    CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            H      H  Colorless needle-like crystals                                                (Ethanol)                                                                              189-190 (NMR                                                                        Hydro- chloride       __________________________________________________________________________     *1) NMR (CDCl.sub.3) δ: 7.26-7.00 (m, 5H), 6.78 (s, 1H), 4.40 (s,       1H), 4.0 (br, 2H), 3.30 (d, 1H, J=18Hz), 2.86 (d, 1H, J=17Hz), 2.15 (s,       6H), 1.59 (s, 3H)                                                             *2) NMR (DMSOd.sub.6) δ: 7.35 (d, 2H, J=8.5Hz), 7.14 (d, 2H,            J=8.5Hz), 6.77 (s, 1H), 4.74 (d, 1H, J=6Hz), 3.85-3.60 (m, 1H), 3.20-2.95     (m, 2H), 2.15 (s, 3H), 2.10 (s, 3H)                                           *3) NMR (CDCl.sub.3) δ: 7.20 (d, 2H, J=8.5Hz), 6.88 (d, 2H,             J=8.5Hz), 6.83 (s, 1H), 4.90 (d, 1H, J=7.0Hz), 3.75-3.50 (m, 1H), 3.24        (dd, 1H, J=15Hz, 7.0Hz), 3.95 (dd, 1H, J=15Hz, 3Hz), 2.19 (s, 6H)             *4) NMR (CDCl.sub.3 -DMSOD.sub.6) δ: 7.05 (s, 4H), 6.80 (s, 1H),        6.60 (s, 1H), 4.78 (d, 1H, J=7.5Hz), 3.65 (m, 1H), 3.15-2.90 (m, 2H), 2.2     (s, 3H), 2.12 (s, 6H)                                                         *5) NMR (DMSOd.sub.6) δ: 2.17 (s, 6H), 2.40 (s, 3H), 2.91 (dd, 1H,      J=15Hz, 6Hz), 3.60 (dd, 1H, J=15Hz, 12Hz), 3.80-4.17 (m, 1H), 4.80-5.10       (m, 1H), 6.95 (s, 1H), 7.10-7.30 (m, 3H), 7.43-8.00 (m, 3H), 9.10 (br, 1H     *6) NMR (DMSOd.sub.6) δ: 2.01 (s, 3H), 2.06 (s, 3H), 2.30-3.20 (m,      5H), 4.21 (m, 1H), 6.46 (s, 1H), 6.73 (s, 1H), 6.87 (d, 2H, J=8Hz), 7.13      (d, 2H, J=8Hz)                                                                *7) NMR (CDCl.sub.3) δ: 7.40-7.18 (m, 3H), 7.10-6.90 (m, 3H), 4.90      (d, 1H, J=7.5Hz), 3.84-3.60 (m, 1H), 3.50-3.10 (m, 2H, 2.20 (s, 3H)           *8) NMR (CDCl.sub.3) δ: 7.25-7.10 (m, 3H), 6.92 (m, 2H), 6.80 (s,       1H), 4.88 (d, 1H, J=7.5Hz), 3.68 (td, 1H, J=7.0Hz, 3Hz), 3.25 (dd, 1H,        J=15Hz, 7.5Hz), 2.95 (dd, 1H, J=15Hz, 3Hz), 2.80-2.35 (m, 2H), 1.20 (t,       3H)                                                                           *9) NMR (CDCl.sub.3 -DMSOd.sub.6) δ: 8.60-7.70 (br, 4H), 6.83 (s,       1H), 4.73 (d, 1H, J=6Hz), 3.50-3.20 (m, 1H), 2.85-2.60 (m, 2H), 2.18 (s,      3H), 2.12 (s, 3H), 2.20-0.80 (m, 10H)                                         *10) NMR (CDCl.sub.3) δ: 2.18 (s, 6H), 2.95 (dd, 1H, J=15Hz, 3Hz),      3.25 (dd, 1H, J=16.5Hz, 7.5Hz), 3.68 (dd-d, 1H, J=7.5Hz, 7.5Hz, 3.0Hz),       4.89 (d, 1H, J=7.5Hz), 6.80 (s, 1H), 6.87-7.03 (m, 2H), 7.13-7.30 (m, 3H)     *11) NMR (CDCl.sub.3 -DMSOd.sub.6) δ: 7.40-7.15 (m, 5H), 6.83 (s,       1H), 6.68 (s, 2H), 4.85 (d, J=7.5Hz, 1H), 3.90-3.60 (m, 1H), 3.25-3.10 (m     2H), 2.18 (s, 6H)                                                             *12) NMR (DMSOd.sub.6) δ: 2.06 (s, 3H), 2.11 (s, 3H), 2.30-3.30 (m,     5H), 4.70 (m, 1H), 6.50 (s, 1H), 6.79 (s, 1H), 7.20-7.40 (m, 5H),             7.00-8.20 (broad, 6H)                                                         *13) NMR (CDCl.sub.3) δ: 2.20 (3H, s), 2.99 (1H, dd, J=16.5Hz, 3Hz)     3.23 (1H, dd, J=16.5Hz, 7.5 Hz), 3.70 (1H, ddd, J=7.5Hz, 7.5Hz, 3Hz), 4.9     (1H, d, J=7.5Hz), 6.89 (1H, d, J=6Hz), 6.93 (1H, d, J=6.0Hz), 7.20 (4H, s     *14) NMR (DMSOd.sub.6) δ: 2.20 (3H, s), 3.03 (1H, dd, J=15Hz,           7.5Hz), 3.27-4.03 (2H, m), 4.67-4.93 (1H, brm), 6.90 (2H, ABq, J=22.5Hz,      8.5Hz), 7.23--7.63 (5H, m), 7.67-8.03 (3H, brm), 9.77-10.07 (1H, brm)         *15) NMR (DMSOd.sub.6) δ: 2.02 (s, 3H), 2.10 (s, 3H), 2.15-3.15 (m,     5H), 4.35 (m, 1H), 6.50 (s, 2H), 6.82 (s, 1H), 7.20-7.50 (m, 4H),             8.20-10.00 (broad, 5H)                                                        *16) NMR (DMSOd.sub.6) δ: 2.01 (s, 3H), 2.10 (s, 3H), 2.20-3.20 (m,     5H), 4.65 (s, 1H), 5.97 (s, 2H), 6.45 (s, 1H), 6.50-7.00 (m, 4H),             7.90-9.00 (broad, 4H)                                                         *17) NMR (DMSOd.sub.6) δ: 0.98 (s, 3H), 0.50-2.00 (m, 13H), 2.09 (s     3H), 2.15 (s, 3H), 2.55 (d, 1H, J=15Hz), 3.94 (d, 1H, J=15Hz), 4.23 (s,       1H), 6.90 (s, 1H), 8.2-9.5 (broad, 4H)                                   

Example 24

To a chloroform solution containing 31.8 g of1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenylpropyl)-1H-indenehydrochloride and 15.2 g of triethylamine dissolved in 200 ml ofchloroform was added dropwise 13.56 g of chloroacetyl chloride underice-cooled with stirring condition. After finished the dropwiseaddition, the reaction mixture was stirred at 25° C. for 3 hours. Afterthe reaction was completed, the reaction mixture was washed with 100 mlof 1N-hydrochloric acid aqueous solution, then washed three times with100 ml of water each time. After dried with anhydrous magnesium sulfate,the reaction mixture was concentrated by evaporating the solvent under areduced pressure. The residue thus obtained was recrystallized fromdiethyl ether-n-hexane to obtain 14.7 g of1-chloroacetylamino-2,3-dihydro-4-methyl-6-(1-phenylpropyl)-7-hydroxy-1H-indene.Colorless powdery crystals. Melting point: 172°-174° C.

Examples 46-49

By a method similar to that described in Example 45, and by using asuitable starting material, there were prepared compounds of Examples46-49 as shown in Table 5 as follows:

                                      TABLE 5                                     __________________________________________________________________________     ##STR84##                                                                                                           Crystal form                                                                           Melting                       Example                                (Recrystalli-                                                                          point                         No.  R.sup.1  R.sup.2                                                                         R.sup.3                                                                          R.sup.4   R.sup.5 R.sup.6                                                                         zation solvent)                                                                        (°C.)                  __________________________________________________________________________    46   H        H CH.sub.3                                                                          ##STR85##                                                                              NHCOCH.sub.2 Cl                                                                       H Colorless powdery crystals                                                    (n-Hexane)                                                                             131-132                       47                                                                                  ##STR86##                                                                             H CH.sub.3                                                                         CH.sub.3  NHCOCH.sub.2 Cl                                                                       H Colorless needle-like crystals                                                (Ethanol)                                                                              189-190                       48                                                                                  ##STR87##                                                                             H CH.sub.3                                                                         CH.sub.3  NHCOCH.sub.2 Cl                                                                       H Colorless powdery crystals                                                    (Ethanol)                                                                              123-124                       49                                                                                  ##STR88##                                                                             H CH.sub.3                                                                         CH.sub.3  NHCOCH.sub.2 Cl                                                                       H Colorless needle-like crystals                                                (Ethanol)                                                                              186-187                       __________________________________________________________________________

Example 50

6.64 Grams of1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indenewas dissolved in 100 ml of acetonitrile. Under stirring condition, 9.27g of 4-(3-chlorophenyl)piperazine was added thereto, then the reactionmixture was refluxed for 2 hours. After the reaction was completed, thereaction mixture was ice-cooled and an excess of4-(3-chlorophenyl)piperazine being separated was removed by filtration,the filtrate thus obtained was concentrated under a reduced pressure.The residue thus obtained was recrystallized from ethanol to obtain 8.10g of1-[4-(3-chlorphenyl)-1-piperazinyl]-acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene.Colorless powdery crystals. Melting point: 125°-126° C.

Examples 51-65

By a method similar to that described in Example 50, and by using asuitable starting material, there were prepared compounds of Examples51-65 as shown in Table 6 as follows.

                                      TABLE 6                                     __________________________________________________________________________     ##STR89##                                                                                                                   Crystal                        Ex-                                            form                           am-                                            (Recrys-                                                                            Melting                  ple                                            tallization                                                                         point                    No.                                                                              R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                          R.sup.4   R.sup.5                R.sup.6                                                                         solvent                                                                             (°C.)                                                                       salt                __________________________________________________________________________    51 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR90##             H Colorless powdery crystals                                                    Ethanol)                                                                            157-158                  52 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR91##             H Colorless powdery crystals                                                    Ethanol)                                                                            103.5-106                53 H  H  CH.sub.3                                                                          ##STR92##                                                                               ##STR93##             H Colorless powdery crystals                                                    Ethanol)                                                                            131-132                  54 H  H  CH.sub.3                                                                          ##STR94##                                                                               ##STR95##             H Colorless powdery crystals                                                    Ethanol)                                                                            106-107                  55 H  H  CH.sub.3                                                                          ##STR96##                                                                               ##STR97##             H Colorless powdery crystals                                                    Acetone)                                                                            165-166                                                                            Dihydro-                                                                      chloride            56 H  H  CH.sub.3                                                                          ##STR98##                                                                               ##STR99##             H Colorless powdery crystals                                                    Ethanol)                                                                            156                      57 H  H  CH.sub.3                                                                          ##STR100##                                                                              ##STR101##            H Colorless powdery crystals                                                    Acetone)                                                                            184.5-186                                                                          Hydro- chloride     58 H  H  CH.sub.3                                                                          ##STR102##                                                                              ##STR103##            H Colorless plate-like                                                          crystals (Ethanol)                                                                  149-150                  59 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR104##                                                                              ##STR105##            H Colorless powdery crystals                                                    Ethanol)                                                                            130-131                  60 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR106##            H Colorless powdery crystals                                                    Ethanol)                                                                            210-211                  61 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR107##            H Colorless powdery crystals                                                    Ethanol)                                                                            201-202                  62 H  H  CH.sub.3                                                                         CH.sub.3                                                                                 ##STR108##            H Colorless needle-like                                                         crystals (Ethanol)                                                                  174-176                                                                            Hydro- chloride     63 H  H  CH.sub.3                                                                         CH.sub.3                                                                                 ##STR109##            H Colorless needle-like                                                         crystals (Ethanol)                                                                  196-198                                                                            Hydro- chloride     64 H  H  CH.sub.3                                                                          ##STR110##                                                                              ##STR111##            H Colorless powdery crystals                                                    Diethyl ether-n- hexane)                                                            177-178                  65 H  H  CH.sub.3                                                                          ##STR112##                                                                              ##STR113##            H Colorless powdery crystals                                                    Diethyl ether-n- hexane)                                                            141-143.0                                                                          Hydro- chloride     __________________________________________________________________________

Examples 66-101

By a method similar to that described in Example 50, and by using asuitable starting material, there were prepared compounds of Examples66-101 as shown in Table 7 as follows.

    TABLE 7      ##STR114##               Crystal           form         (Recrystal- Melting Example        lization point No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6     R.sup.7 solvent) (°C.) Salt                  66 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3      ##STR115##      H H Colorlesspowderycrystals(Ethanol) 142-143 --  67 CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3      ##STR116##      H H Colorlessneedle-likecrystals(Ethanol)  84-87 --  68 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR117##      H CH.sub.3 Colorlesspowderycrystals(Ethanol) 170-171 --      69     ##STR118##      H CH.sub.3 CH.sub.3      ##STR119##      H H Colorlesspowderycrystals(Ethanol) 134.5-136.5 Semi-fumarate  70      ##STR120##      H CH.sub.3 CH.sub.3      ##STR121##      H H Colorlessneedle-likecrystals(Ethanol) 204-205 --  71 H H CH.sub.3     CH.sub.3      ##STR122##      H H Colorlesspowderycrystals(Ethanol) 152-157 Oxalate      72     ##STR123##      H CH.sub.3 CH.sub.3      ##STR124##      H H Colorlessneedle-likecrystals(Ethanol) 178.5-179 --      73     ##STR125##      H CH.sub.3 CH.sub.3      ##STR126##      H H Colorlessprism-likecrystals(Ethanol) 174-176 --  74 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR127##      H H Colorlessprism-likecrtstaks (Diethylether)  83-84 Oxalate  75     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3      ##STR128##      H H Colorlesspowderycrystals(Ethanol) 195-196 Dihydro-chloride  76     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3      ##STR129##      H H Colorlesspowderycrystals(Ethanol) 112(decomposed) --  77 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR130##      H H Colorlessneedle-likecrystals(Ethanol-diethylether) 104-108 --  78     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3      ##STR131##      H H  Colorlesspowderycrystals(Ethanol) 216-219 Dihydro-chloride  79      ##STR132##      H CH.sub.3 CH.sub.3      ##STR133##      H H Colorlesspowderycrystals(Ethanol) 128-130 Semi-fumarate  80      ##STR134##      H CH.sub.3 CH.sub.3      ##STR135##      H H Colorlessneedle-likecrystals(Ethanol) 155-156 --      81     ##STR136##      H CH.sub.3 CH.sub.3      ##STR137##      H H Colorlessneedle-likecrystals(Ethanol) 143-144 --  82 CH.sub.3     CH.sub.3 CH.sub.3 H      ##STR138##      H H Colorlessprism-likecrystals(Ethanol-diethylether) 167-168 Semi-fumar     ate      83 CH.sub.3 CH.sub.3 CH.sub.3     ##STR139##      ##STR140##      H H Colorlessprism-likecrystals(Ethanol-diethylether) 135-137 Dihydro-ch     loride      84 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3     ##STR141##      H H Colorlesspowderycrystals(Diethylether--n-hexane) 142-143 Semi-fumara     te      85 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3     ##STR142##      H H Colorlessneedle-likecrystals(Ethanol) 125-126.5 --  86 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR143##      H H Colorlesspowderycrystals(Ethanol-water) 125-126 --  87 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR144##      H H Colorlessneedle-likecrystals(Ethanol) 160-161.5 --  88 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR145##      H H Colorlessneedle-likecrystals(Ethanol) 187-188 --  89 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR146##      H H Colorlessflake-likecrystals(Ethanol) 205- 207  90 CH.sub.3 CH.sub.3     CH.sub.3 CH.sub.3      ##STR147##      H H Colorlessneedle-likecrystals(Ethanol-water) 168-170 --  91 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR148##      H H Colorlessneedle-likecrystals(Ethanol-water) 177-178 --  92 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR149##      H H Colorlessneedle-likecrystals(Ethanol-water) 176-177 --  93 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR150##      H H Colorlessneedle-like crystals(Ethanol-water) 107-108 --  94     CH.sub.3 H CH.sub.3 CH.sub.3      ##STR151##      H H Colorlessneedle-likecrystals(Ethanol-water) 224-226      95     ##STR152##      H CH.sub.3 CH.sub.3      ##STR153##      H H Colorlessneedle-likecrystals(Ethylacetate--n-hexane) 187-189 --  96     CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3      ##STR154##      H H Colorlessneedle-likecrystals(Ethanol) 165-166 --  97 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR155##      H H Colorlessneedle-likecrystals(Ethanol) 166-167 --  98 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR156##      H H Colorlessneedle-likecrystals(Ethanol) 178-179 --  99 CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR157##      H H Colorlessneedle-likecrystals(Ethanol) 197-198.5 --  100  CH.sub.3     CH.sub.3 CH.sub.3 CH.sub.3      ##STR158##      H H Colorlessneedle-likecrystals(Ethanol-water) 172-174 --  101      ##STR159##      CH.sub.3 CH.sub.3 CH.sub.3      ##STR160##      H CH.sub.3 Colorlesspowderycrystals(Ethanol) 139.5-141.0 Fumarate

Example 102

3.63 Grams of 2-pyrrolidone was dissolved in 40 ml of dimethylformamide,then to this solution was added gradually 1.71 g of 60%-sodium hydride,and the whole mixture was stirred for 30 minutes. To this suspension wasadded 4.00 g of1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indeneand the reaction mixture was stirred at room temperature for 30 minutes.After the reaction was completed, the reaction mixture was poured in 100ml of ice-water, and extracted with 200 ml of methylene chloride. Theextract was washed with water, then dried with anhydrous magnesiumsulfate and the solvent was removed by evaporation under a reducedpressure. The residue thus obtained was purified by a silica gel columnchromatography (eluent: ethyl acetate: n-hexane=1:2), and recrystallizedfrom ethanol to obtain 2.27 g of2,3-dihydro-7-hydroxy-1-(2-pyrrolidon-1-yl)acetylamino-2,2,4,6-tetramethyl-1H-indene.Colorless needle-like crystals. Melting point: 165°-168° C.

Example 103

A mixture of 1.07 g of 4-methylpiperazine, 1.50 g of1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indeneand 24 ml of acetonitrile was refluxed for 2 hours. After the reactionwas completed, the reaction mixture was ice-cooled, and the crystalsbeing separated were removed by filtration, and the filtrate wasconcentrated under a reduced pressure. The residue thus obtained waspurified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2), next recrystallized from ethanol to obtain 1.20 g of2,3-dihydro-7-hydroxy-1-(4-methyl-1-piperazinyl)acetylamino-2,2,4,6-tetramethyl-1H-indene.Colorless needle-like crystals. Melting point: 189°-190° C.

Examples 104-111

By a method similar to that described in Example 103, and by usingsuitable starting materials, there were prepared compounds of Examples104-111 as shown in Table 8 as follows.

                                      TABLE 8                                     __________________________________________________________________________     ##STR161##                                                                                                           Crystal form                                                                          Melting                       Example                                 (Recrystalli-                                                                         point                         No.  R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                          R.sup.4   R.sup.8         zation solvent)                                                                       (°C.)                  __________________________________________________________________________    104  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR162##     Colorless needle-like crystals                                                (Ethanol)                                                                             168-169                       105  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR163##     Colorless needle-like crystals                                                (Ethanol)                                                                             198-199                       106  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR164##     Colorless powdery  crystals                                                   (Ethanol)                                                                             250-252                       107  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR165##     Colorless needle-like crystals                                                (Ethanol)                                                                             147.5-148                     108  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR166##     Colorless needle-like crystals                                                (Ethanol)                                                                             127-128                       109  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR167##     Colorless needle-like crystals                                                (Ethanol)                                                                             209-211 (decomposed)          110  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                                 ##STR168##     Colorless needle-like crystals                                                (Ethanol)                                                                             242 (decomposed)              111  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                          ##STR169##                                                                              ##STR170##     Colorless needle-like crystals (                                              --Hexane)                                                                             129-131                       __________________________________________________________________________

Example 112

To an acetonitrile solution containing 2.50 g of1-amino-2,3-dihydro-2,2,4,6-tetramethyl-7-hydroxy-1H-indenehydrochloride, 4.33 ml of triethylamine in 30 ml of acetonitrile wasadded 3.0 g of 1-chloroacetyl-4-(3-methoxyphenyl)piperzine, and thereaction mixture was refluxed for 10 hours. After the reaction wascompleted, the solvent was removed by evaporation, and the residue thusobtained was dissolved in 200 ml of chloroform, then this chloroformsolution was washed with water and dried with anhydrous magnesiumsulfate. The solvent was again removed under a reduced pressure toobtain the residue, then said residue was purified by a silica gelcolumn chromatography (eluent: ethyl acetate: n-hexane=1:2).Recrystallized from ethanol to obtain 0.90 g of1-(2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1yl)-aminoacetyl-4-(3-methoxyphenyl)piperazine.Colorless flake-like crystalas. Melting point: 164.5°-166.0° C.

Example 113

By a method similar to that described in Example 112, and using asuitable starting material, the following compound was prepared.

1-(2,3-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl)aminoacetyl-4-(3-chlorophenyl)piperazine

Colorless powdery crystals (from ethanol)

melting point: 144.0°-145.5° C.

Example 114

To a solution containing 5.00 g of1-[4-(3-chlorophenyl)-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indeneand 100 ml of diglyme (diethylene glycol dimethyl ether) was added 4.3 gof lithium aluminum hydride gradually, under stirring condition. Thenthe reaction mixture was refluxed for 3 hours. After the reaction wascompleted, the reaction mixture was ice-cooled, then ice-water was addedto the reaction mixture so as to decompose an excess amount of lithiumaluminum hydride. The whole mixture was filtered, and the filtrate wasextracted with 200 ml of methylene chloride, and the extract was washedwith water, dried with anhydrous magnesium sulfate, then the solvent wasremoved by evaporation under a reduced pressure. The residue thusobtained was dissolved in 50 ml of ethanol, then an ethanol solutioncontaining 1.31 g of fumaric acid was added thereto and concentrated todryness under a reduced pressure. Recrystallized from ethanol to obtain2.3 g of1-{2-[4-(3-chlorophenyl)-1-piperazinyl]ethylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene fumarate. Colorless powdery crystals.

Melting point: 144°-146° C.

Example 115

By a method similar to that described in Example 114, using a suitablestarting material, there was prepared the following compound.

1-{2-[4-(3-Methoxyphenyl)-1-piperazinyl]-ethylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indenefumarate. Colorless powdery crystals (from ethanol). Melting point:122°-125° C.

Example 116

To a solution containing 22.65 g of1-amino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indenehydrochloride and 15.2 g of triethylamine in 200 ml of chloroform wasadded dropwise 32.76 g of [4-(3-chlorophenyl)-1-piperazinyl]acetylchloride, under ice-cooled condition with stirring. After finished thedropwise addition, the reaction mixture was stirred at 25° C. for 3hours. After the reaction was completed, the reaction mixture was washedwith 100 ml of 1N-hydrochloric acid aqueous solution, then furtherwashed three times with 100 ml of water, then dried with anhydrousmagnesium solfate. The solvent was removed by evaporation under areduced pressure, the residue thus obtained was recrystallized fromethanol of obtain 17.6 g of1-{[4-(3-chlorophenyl)-1-piperazinyl]acetylamino}-2,3-dihydro-2,2,4,6-tetramethyl-7-hydroxy-1H-indene.Colorless powdery crystals. Melting point: 125°-126° C.

By a method similar to that described in Example 115, and using suitablestarting materials, there were prepared compounds of Examples 51-111.

Example 117

To a solution containing 1.77 g of1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene and 2 ml oftriethylamine in 100 ml of chloroform was added dropwise 2.23 g of octylchloride at room temperature. Then the reaction mixture was stirred atthe same temperature for 4 hours. The reaction mixture was washed with adiluted hydrochloric acid, water, an aqueous solution saturated withsodium bicarbonate, water and an aqueous solution saturated with sodiumchloride in this order, then dried with anhydrous sodium sulfate. Thesolvent was removed by evaporation and the residue thus obtained wasdissolved in ethanol, then an ethanol saturated with hydrogen chloridegas was added thereto form a hydrochloride. Recrystallized formacetonitrile to obtain 0.49 g of2,3-dihydro-1-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochloride.Colorless needle-like crystals. Melting point: 120°-121° C.

By a method similar to that described in Example 117, and by usingsuitable starting materials, there were prepared compounds of Examples114 and 115, further prepared compounds of Examples 118-121, 124 asmentioned below.

Example 118

A solution containing 1.76 g of2,3-dihydro-4.6-dimethyl-7-hydroxy-1H-inden 1-one and 25.8 g ofn-octylamine in 100 ml ethanol was refluxed for 8 hours. After cooledthe reaction mixture to room temperature, 1 g of sodium born hydride wasadded thereto, then the whole reaction mixture was further stirred atroom temperature for 1 hour. The reaction mixture was concentrated todryness, and the residue thus obtained was dissolved in 100 ml of water,then this solution was acidified with a concentrated hydrochloric acid,next the pH of this solution was adjusted by adding an aqueous solutionsaturated with sodium acetate to about pH 9. The separated matter wasextracted with ethyl acetate, washed with water and dried. The solventwas removed by evaporation and the residue thus obtained was dissolvedin 100 ml of ethanol, then an ethanol solution saturated with hydrogenchloride gas was added thereto to form hydrochloride. Recrystallizedfrom acetonitrile to obtain 3.40 g of2,3-dihydro-1n-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochlorideColorless needle-like crystals. Melting point: 120°-121° C.

Example 119-121

By a method similar to that described in Example 118, and by usingsuitable starting materials, there were prepared compounds of Examples119-121 shown in Table 9 as follows.

                                      TABLE 9                                     __________________________________________________________________________     ##STR171##                                                                                                      Crystal form                                                                  (Recrystalli-                                                                        Melting                             Example                            zation point                               No.  R.sup.1                                                                              R.sup.2                                                                         R.sup.3                                                                          R.sup.4                                                                          R.sup.5      R.sup.6                                                                         solvent)                                                                             (°C.)                                                                       Salt                           __________________________________________________________________________    119  H      H CH.sub.3                                                                         CH.sub.3                                                                         NHC.sub.10 H.sub.21                                                                        H Colorless                                                                            124-126                                                                            Hydro-                                                            needle-like chloride                                                          crystals                                                                      (Acetonitrile)                             120                                                                                 ##STR172##                                                                          H CH.sub.3                                                                         CH.sub.3                                                                          ##STR173##  H Colorless powdery crystals (Ethanol)                                                 221-223                                                                            Dihydro- chloride              121                                                                                 ##STR174##                                                                          H CH.sub.3                                                                         CH.sub.3                                                                          ##STR175##  H Colorless needle-like crystals                                                (Ethanol)                                                                            122-123                             __________________________________________________________________________

Example 122

200 Grams of6-chloroacetylaminomethyl-2,3-dihydro-7-hydroxy-4-methyl-1H-indene-1-one,77.9 g of hydroxylamine hydrochloride, 300 ml of pyridine and 1,800 mlof ethanol were refluxed for 3 hours. After the reaction was completed,the solvent was removed by evaporation under a reduced pressure, then tothe residue thus obtained was added 2 liters of water and the mixturewas stirred vigorously, cooled and crystallized. The crystals werecollected by filtration, washed with water, and recrystallized fromwater to obtain 167 g of(2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-indene-6yl)-methylaminocarbonylmethylpyridiniumchloride. Colorless flake-like crystals. Melting point: 279° C.(Decomposed).

Example 123

10 Grams of(2,3-dihydro-7-hydroxy-1-hydroxyimino-4-methyl-1H-indene-6-yl)methylaminocarbonylmethylpyridiniumchloride, 200 ml of acetic acid and 1.0 g of platinum oxide weresubjected to catalytic hydrogenation under 3 atmospheric hydrogen gaspressure at room temperature for 8 hours. After the hydrogenation wascompleted, the catalyst was removed by filtration, and the filtrate wasconcentrated to dryness under a reduced pressure. The residue thusobtained was dissolved in 100 ml of methanol and under ice-cooledcondition, a methanol solution saturated with hydrogen chloride gas wasadded thereto so as to adjust the pH of the solution to about pH 1, thenthe said solution was concentrated to dryness under a reduced pressure.The residue thus obtained was recrystallized from ethanol-diethyl etherto obtain 4.8 g of1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-piperindinylacetylaminomethyl-1H-indenedihydrochloride. Colorless powdery crystals. Melting point: 146° C.(decomposed).

Example 124

0.21 Gram of 4-(3-chlorophenyl)-1-(2,3-epoxypropyl)piperazine was addedto a solution containing 0.21 g of1-amino-2,3-dihydro-7-hyroxy-2,2,4,6-tetramethyl-1H-indene hydrochloridein 10 ml of ethanol solution, and the mixture was refluxed for 5 hours.After the reaction was completed, the reaction mixture was concentratedby removing the solvent under a reduced pressure, the residue thusobtained was alkalified with 10%-sodium bicarbonate aqueous solution,then extracted with 100 ml of methylene chloride. The extract was washedthere times with 100 ml of water each time, then dried with anhydrousmagnesium sulfate. The methylene chloride extract was concentrated byremoving the solvent under a reduced pressure, and the residue waspurified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 0.21 g of1-{3-[4-(3-chlorophenyl)-1-piperazinyl]-2-hydroxypropylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene.

NMR (CDCl₃) δ: 7.14 (t, 1H0, 6.90-6.70 (m, 4H), 4.60-3.70 (br., 2H),4.20 (s, 1H), 3.90 (m, 1H), 3.20 (t, 6H, 2.90-2.30 (m, 8H), 2.18 (s, 3H,2.80 (s, 3H), 1.20 (s, 2H), 0.85 (s, 3H).

Example 125

2.60 Grams of 4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene,0.26 g of 10%-palladium carbon and 50 ml of acetic acid werecatalytically hydrogenated under 4 atmospheric hydrogen gas pressure atroom temperature. After completed the hydrogenation, the catalyst wasseparated from the reaction mixture and was washed with ethanol. Thefiltrate and the above-mentioned washing ethanol liquor were combinedtogether and concentrated. The residue thus obtained was purified by asilica gel column chromatography (eluent: ethyl acetate: n-hexane=1:5)to obtain 0.67 g of1-amino-2-phenyl-2-benzyloxy-4,6-dimethyl-2,3-dihydro-7-hydroxy-1H-indene(Compound A) and 0.37 g of1-amino-2-phenyl-2-hydroxy-4,6-dimethyl-2,3-dihydro-7-hydroxy-1H-indene(Compound B) were obtained.

Compound A: Light yellow prism-like crystals (recrystallized fromethanol) Melting point: 166°-167° C.

Compound B: Colorless needle-like crystals (recrystallized from ethanol)Melting point: 151°-153° C.

Example 126

7.04 Grams of 1-chloroacetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene was dissolved in 200 ml ofacetonitrile, then 10 ml of triethylamine and 5.0 g ofm-methoxyphenylpiperazine were added thereto. The reaction mixture wasrefluxed for 2 hours. The reaction mixture was concentrated to drynessunder a reduced pressure, and to the residue thus obtained was added 100ml of water, then the pH of this solution was adjusted with an aqueoussolution saturated with sodium bicarbonate to about pH=8. This solutionwas extracted with 500 ml of ethyl acetate, and the extract was washedwith water, concentrated to dryness under a reduced pressure. Theresidue thus obtained was boiled with ethanol, and the ethanol-insolublematter was collected by filtration and recrystallized from ethanol toobtain 3.9 g of2,3-dihydro-7-hydroxy-1-[4-(3-methoxyphenyl-1-piperazinyl)]carbonylamino-2,2,4,6-tetramethyl-1H-indene.Colorless powdery crystals. Melting point: 206°-208° C.

NMR (CDCl₃ -DMSO-d₆) δ: 1.10 (s, 3H), 1.23 (s, 3H), 2.10 (s, 3H), 2.15(s, 3H), 2.46 (d, 1H, J=15 Hz), 2.92 (d, 1H, J=15 Hz), 3.05-3.30 (m,4H), 3.50-3.65 (m, 4H), 3.76 (s, 3H), 4.46 (d, 1H, J=7.5 Hz), 6.25-6.60(m, 3H), 6.74 (s, 1H), 7.14 (t, 1H, J=9 Hz), 7.50 (m, ₁ H).

The above-mentioned ethanol extract was concentrated under a reducedpressure, to the residue, to the residue thus obtained was added atethanol solution of fumaric acid to adjust the pH of the solution toabout pH=4-5, then concentrated to dryness under a reduced pressure. Theresidue thus obtained was recrystallized from ethanol to obtain 5.2 g of2,3-dihydro-7-hydroxy-1-[4-(3-methoxyphenyl-1-piperazinyl)]-acetylamino-2,2,4,6-tetramethyl-1H-indenefumarate. Colorless powdery crystals. Melting point: 167°-169° C.

NMR (CDCl₃ -DMSO-d₆) δ: 1.13 (s, 3H, 1.26 (s, 3H), 2.10 (s, 3H), 2.18(s, 3H), 2.48-2.92 (m, 6H), 3,10-3.34 (m, 6H), 3.78 (s, 3H), 4.68 (d,1H, J=7.5 Hz), 6.30-6.60 (m, 3H), 6.74 (s, 2H), 6.80 (s, 1H), 7.15 (t,1H, J=9 Hz), 8.08 (d, 1H, J=7.5 Hz), 8.70-10.0 (br., 2H).

The pharmacological activities of 2,3-dihydro-1H-indene derivatives andsalts thereof represented by the general formula (1) are shown asfollows.

Pharmacological Tests

Test compounds

1).1-[4-(3-Chlorophenyl-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene

2).1-[4-(3-Methoxyphenyl)-1-piperazniyl]acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-methylpropyl)-1H-indenedihydrochloride

3).1-[4-(3,5-Dichlorophenyl)-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-methylpropyl)-1H-indene

4).1-[4-(3-Chlorophenyl)-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-methylpropyl)-1H-indenehydrochloride

5).1-[4-(3-Chlorophenyl)-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-4,6-dimethyl-1H-indenehydrochloride

6).1-[4-(3-Methoxyphenyl)-1-piperazinyl]acetylamino-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene

7).2,3-Dihydro-7-hydroxy-4-methyl-1-(4-methyl-1-piperazinyl)acetylamino-6-(1-methylpropyl)-1H-indene

8). 1-Amino-2-phenyl-4,6-dimethyl-7-hydroxy-2,3-dihydro-1H-indene

9).1-Amino-2-(2-methylphenyl)-4,6-dimethyl-7-hydroxy-2,3-dihydro-1H-indene

10).1-Amino-2-(4-chlorophenyl)-4,6-dimethyl-7-hydroxy-2,3-dihydro-1H-indene

11).1-[4-(3-Chlorphenyl)-1-piperazinyl]acetylamino-4-methyl-6-(1-phenylpropyl)-7-hydroxy-2,3-dihydro-1H-indene

12).1-[4-(3-Methoxyphenyl)-1-piperazinyl]acetylamino-2-cyclohexyl-4,6-dimethyl-7-hydroxy-2,3-dihydro-1H-indene

13).1-[4-(3-Methoxyphenyl)-1-piperazinyl]amino-2,2,4,6-tetramethyl-7-hydroxy-2,3-dihydro-1H-indene

14).1-Amino-4-methyl-6-(1-cyclohexylpropyl)-7-hydroxy-2,3-dihydro-1H-indene

15).1-(4-Methyl-1-pierazinyl)acetylamino-2,2,4,6-tetramethyl-7-hydroxy-2,3-dihydro-1H-indene

16).1-Amino-2-methyl-2-phenyl-4,6-dimethyl-7-methoxy-2,3-dihydro-1H-indene

17).1-{2-[4-(3-Chlorophenyl)-1-piperazinyl]ethylamino}-2,2,4,6-tetramethyl-7-hydroxy-2,3-dihydro-1H-indene

18).1-(2,3-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene-1-yl)aminoacetyl-4-(3-chlorophenyl)-piperazine

19).1-(Pyrrolidinylacetylamino)-7-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1H-indene

20).1-(Piperidinylacetylamino)-7-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1H-indene

21).2,3-Dihydro-1-limino-2-phenyl-2-hydroxy-4,6-dimethyl-7-hydroxy-1H-indene

22).2,3-Dihydro-1-[2-(dimethylamino)ethylamino]-2-phenyl-4,6-dimethyl-7-hydroxy-1H-indene

23). 2,3-Dihydro-1-benzylamino-2-phenyl-4,6-dimethyl-7-hydroxy-1H-indene

24).2,3-Dihydro-1-amino-2-phenyl-2-benzyloxy-4,6-dimethyl-7-hydroxy-1H-indene

25). 2,3-Dihydro-1-amino-3-phenyl-4,6-dimethyl-7-hydroxy-1Hpindene

26).2,3-Dihydro-1-[4-(3-methoxyphenyl)-1-piperazinyl]-acetylamino-2,2,4-trimethyl-7-hydroxy-1H-indene

27).2,3-Dihydro-1-[4-(4-methoxyphenyl)-1-piperazinyl]-acetylamino-2,2,4,6-tetramethyl-7-hydroxy-1H-indene

28).2,3-Dihydro-1-[4-(4-methoxybenzoyl)-1-piperazinyl]-acetylamino-2,2,4,6-tetramethyl-7-hydroxy-1H-indene

29).2,3-Dihydro-1-[4-(3-methoxyphenyl)-1-piperazinyl]-acetylamino-2,2,4,6-tetramethyl-7-methoxy-1H-indene

30).2,3-Dihydro-1-[4-(2-hydroxyethyl)-1-piperazinyl]acetylamino-2,2,4,6-tetramethyl-7-hydroxy-1H-indene

31).2,3-Dihydro-1-[4-(2,4,6-trimethylphenyl)-1-piperazinyl]acetylamino-2,2,4,6-tetramethyl-7-hydroxy-1Hpindene

32).2,3-Dihydro-2-(2-chlorohexyl)-1-amino-4,6-dimethyl-7-hydroxy-1H-indene

33). 2,3-Dihydro-1-amino-2-phenyl-4-chloro-6-methyl-7-hydroxy-1H-indene

34).2,3-Dihydro-1-[4-(3-chlorophenyl)-piperazinly]acetylamino-2-(2-methylphenyl)-4,6-dimethyl-7-hydroxy-1H-indene

35). 2,3-Dihydro-1-amino-2-benzyl-4,6-dimethyl-7-hydroxy-1H-indene

36).2,3-Dihydro-1-amino-2-(4-methoxybenzyl)-4,6-dimethyl-7-hydroxy-1H-indene

37).2,3-Dihydro-2,2,4,6-tetramethyl-1-(4-pyrrolidinylcarbonylmethyl-1-piperazinyl)-acetylamino-7-hydroxy-1H-indene

38).2,3-Dihydro-2,4,6-trimethyl-2-phenyl-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-7-methoxy-1H-indene

39).2,3-Dihydro-2,2,4,6-tetramethyl-1-[4-(2-ethoxyphenyl)-1-piperazinyl]acetylamino-7-hydroxy-1H-indene

40).2,3-Dihydro-2,2,4,6-tetramethyl-1-[4-2,5-dichlorophenyl)-1-piperazingy]acetylamino-7-hydroxy-1H-indene

41).2,3-dihydro-2,2,4,6-tetramethyl-1-[4-(3-fluorophenyl)-1-piperazinyl]acetylamino-7-hydroxy-1H-indene

42).2,3-Dihydro-2,2,4,6-tetramethyl-1-[4-(3,4-dimethoxyphenyl)-1-piperazinyl]acetylamino-7-hydroxy-1H-indene

43).2,3-Dihydro-2-(4-chlorobenzyl)-1-amino-4,6-dimethyl-7-hydroxy-1H-indene

44).2,3-Dihydro-2-(cyclohexylmethyl)-2,4,6-trimethyl-7-hydroxy-1-amino-1H-indene

45). 2,3-Dihydro-1-amino-2-phenyl-4-methyl-6-bromo-7-hydroxy-1H-indene

Pharmacological Test - 1

Survival test under hypoxic condition

This test was conducted by a procedure similar to that described in"Arch. Int. Pharmacodyn. Ther., Vol. 233, page 137, (1987)".

ICR-strain male mice (weighing 20 to 30 g) were used as test animals.One test group was consisting of four (4) mice. The mice were placed ina glass desiccator with which a stop valve was equipped. Inside pressureof the desiccator was reduced until 210 or 240 mm Hg by sucking theinside air by using a vacuum pump, then the stop valve was closed. Eachof the test compounds was administered orally or intraperitoneally tothe mouse at 15 minutes before the beginning of the vacuum pumpoperation.

Survival time of the test mouse was determined as the length of timebetween the beginning of the vacuum pump operation and the cease ofbreathing of the best mouse.

Activity of the test compound in the survival test was defined as theratio (%) of survival time of the test mouse under hypoxic condition incontrol group (A) and that of in the test group (B) being administeredwith test compound, calculated from the following formula: ##EQU1##wherein

A: survival time of the test mouse in control group

B: survival time of the test mouse being administered with test compound(test group)

The test results are shown in Table 10 below.

                  TABLE 10                                                        ______________________________________                                                                          Ratio of                                    Test       Method of     Dosage   survival                                    compound   administration                                                                              (mg/kg)  time (%)                                    ______________________________________                                         1         Orally        Control  100                                                                  10       151                                                                  30       148                                          2         Intraperitoneally                                                                           Control  100                                                                   3       112                                                                  10       218                                                                  30       158                                          3         Intraperitoneally                                                                           Control  100                                                                  30       139                                          4         Orally        Control  100                                                                  10       119                                                                  30       145                                                                  100      225                                          5         Orally        Control  100                                                                  100      211                                          6         Intraperitoneally                                                                           Control  100                                                                  30       169                                          7         Orally        Control  100                                                                  100      132                                          8         Intraperitoneally                                                                           Control  100                                                                  30       186                                          9         Orally        Control  100                                                                  30       202                                         13         Intraperitoneally                                                                           Control  100                                                                  10       138                                         14         Intraperitoneally                                                                           Control  100                                                                  10       901                                         17         Orally        Control  100                                                                  30       141                                         18         Orally        Control  100                                                                  30       147                                         19         Orally        Control  100                                                                  30       134                                         25         Orally        Control  100                                                                  30       123                                         32         Orally        Control  100                                                                  100      121                                         34         Orally        Control  100                                                                  100      123                                         35         Orally        Control  100                                                                  100      156                                         36         Orally        Control  100                                                                  100      148                                         37         Orally        Control  100                                                                  100      159                                         39         Orally        Control  100                                                                  100      131                                         40         Orally        Control  100                                                                  100      151                                         41         Orally        Control  100                                                                  100      123                                         43         Orally        Control  100                                                                  100      121                                         45         Orally        Control  100                                                                  100      125                                         ______________________________________                                    

Pharmacological Test - 2

Test for determining restoration from disturbance of consciousness inmouse

The test was conducted for determining that whether compounds of thepresent invention will show effects for restoration from disturbance ofconsciousness.

The head of test mouse was fixed on a pillow made of foamed polystyreneresin, by holding the cervical skin of the mouse. The centriciput of thetest mouse was let shocked by falling a cylindrical rod (weighing 20 g)made of polyacrylic resin.

As to the indication of effects for restoration from disturbance ofconsciousness, the length of time appearing righting reflex (RR-time)after giving the shock, and the length of time appearing spontaneousmotor (SM-time) after giving the shock were used.

Each of the test compounds was administered orally or intraperitoneallyin the rate of 0.1 ml/kg of the body weight, at 15 minutes before givingthe shock. To the test mouse of the control group, the same amount ofphysiological saline water was administered.

After the test, the brains of all of the tested mice were subjected topostmortem examination, and those mice showing contused wound in thebrain were excluded from the determination.

The RR-time obtained from the test mouse of control group (C) is definedas 100, and the ratio (%) of the RR-time obtained from the test mouse oftest group (D) to the above-mentioned (C) is calculated from the formulaas follows: ##EQU2##

Similarly, the SM-time obtained from the test mouse of control group (E)is defined as 100, and ratio (%) of the SM-time obtained from the testmouse of test group (F) to the above-mentioned (E) is calculated fromthe formula as follows: ##EQU3##

The results are shown in Table 11 as follows.

                  TABLE 11                                                        ______________________________________                                                            Effects for Restora-                                                          tion from disturbance                                                         of consciousness                                                                        Ratio of                                                                              Ratio of                                Test    Method of    Dosage   RR-time SM-time                                 compound                                                                              administration                                                                             (mg/kg)  (%)     (%)                                     ______________________________________                                         4      Orally       Control  100     100                                                          10       84      80                                       6      Intraperitoneally                                                                          Control  100     100                                                          10       48      46                                                           30       53      61                                      7       Orally       Control  100     100                                                          100      50      63                                       8      Orally       Control  100     100                                                          30       34      29                                      10      Orally       Control  100     100                                                          30       53      37                                      11      Orally       Control  100     100                                                          30       31      38                                      12      Orally       Control  100     100                                                          30       50      50                                      13      Orally       Control  100     100                                                          10       45      73                                      15      Orally       Control  100     100                                                          30       45      41                                      16      Orally       Control  100     100                                                          30       25      24                                      17      Orally       Control  100     100                                                          30       65      60                                      19      Orally       Control  100     100                                                          100      59      46                                      20      Orally       Control  100     100                                                          10       75      67                                      21      Orally       Control  100     100                                                          30       74.5    85.1                                    22      Orally       Control  100     100                                                          30       66.6    78.7                                    23      Orally       Control  100     100                                                          30       70.5    68.6                                    24      Orally       Control  100     100                                                          30       82.3    80.7                                    26      Orally       Control  100     100                                                          30       63      65                                      27      Orally       Control  100     100                                                          30       82      63                                      28      Orally       Control  100     100                                                          30       97      77                                      29      Orally       Control  100     100                                                          30       73      62                                      30      Orally       Control  100     100                                                          30       94      96                                      31      Orally       Control  100     100                                                          30       87      84                                      32      Orally       Control  100     100                                                          30       43.6    49.5                                    33      Orally       Control  100     100                                                          30       64.5    76.9                                    34      Orally       Control  100     100                                                          30       75.1    66.0                                    35      Orally       Control  100     100                                                          30       47.0    38.6                                    36      Orally       Control  100     100                                                          30       75.3    62.9                                    37      Orally       Control  100     100                                                          30       53      53                                      38      Orally       Control  100     100                                                          30       75.3    77.0                                    40      Orally       Control  100     100                                                          30       74      69                                      41      Orally       Control  100     100                                                          30       82.8    72.3                                    42      Orally       Control  100     100                                                          30       59      81                                      43      Orally       Control  100     100                                                          30       66.4    45.9                                    44      Orally       Control  100     100                                                          30       50.8    45.7                                    45      Orally       Control  100     100                                                          30       46.7    33.9                                    ______________________________________                                    

Pharmaceutical compositions according to the present invention,containing 2,3-dihydro-1H-indene derivative or salt thereof representedby the general formula (1), as the active ingredient are illustrated byreferring to the following Examples of Pharmaceutical Preparations.Present invention, however, is not restricted only to these examples.

Example of Pharmaceutical Preparation - 1

    ______________________________________                                        Injection Preparation                                                         ______________________________________                                        1-{3-[4-(3-Chlorophenyl)-1-piperazinyl]-                                                                 220 mg                                             propionyl}amino-7-hydroxy-2,2,4,6-tetra-                                      methyl-2,3-dihydro-lHpindene                                                  Glucose                    250 mg                                             Distilled water for injection                                                                            q.s.                                                                           5 ml                                              ______________________________________                                    

1-{3-[4-(3-Cholophenyl)-1-piperazinyl]propionyl}-amino-7-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1H-indeneand glucose were dissolved in distilled water for injection, then thissolution was filled in an ampule of 5 ml volume. After the air in thefilled ampule was replaced with nitrogen gas, then said filled ampulewas sterilized with steam under the pressure at 121° C. for 15 minutesto obtain the injection preparation having the above-mentionedformulation.

Example of Pharmaceutical Preparation - 2

    ______________________________________                                        Film Coated Tablets                                                           ______________________________________                                        1-(2,3-Dihydro-7-hydroxy-2,2,4,6-tetra-                                                               100 g                                                 methyl-1H-inden-1-yl)aminoacetyl-4-                                           (3-methoxyphenyl)piperazine                                                   Avicel (a trademark for microcrystalline                                                              40 g                                                  cellulose, manufactured by Asahi                                              Chemical Industry Co., Ltd.)                                                  Corn starch             30 g                                                  Magnesium stearate       2 g                                                  TC-5 (a trademark for hydroxypropyl                                                                   10 g                                                  methylcellulose, manufactured by                                              The Shin-Etsu Chemical Co., Ltd.)                                             Polyethylene glycol-6000                                                                               3 g                                                  Castor oil              40 g                                                  Methanol                40 g                                                                          265 g                                                 ______________________________________                                    

1-(2,3-Dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene-1-yl)aminoacetyl-4-(3-methoxyphenyl)piperazine,Avicel, corn starch and magnesium stearate were admixed together andground, then the mixture obtained was shaped into tablets by using atablet machine (R=10 mm). The tablets obtained were coated with a filmcoating consisting of TC-5, polyethylene glycol-6000, castor oil andmethanol to prepare the film coated tablets having the above-mentionedformulation.

Example of Pharmaceutical Preparation - 3

    ______________________________________                                        Ointment Preparation                                                          ______________________________________                                        1-{2-[4-(3-Methoxyphenyl)-1-piperazinyl]-                                                             2 g                                                   ethylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-                                    tetramethyl-1H-indene                                                         Purified lanoline       5 g                                                   White bees wax          5 g                                                   White petrolatum        88 g                                                                          100 g                                                 ______________________________________                                    

White bees wax was warmed to make it a liquid state, then1-{2-[4-(3-methoxyphenyl)-1-piperazinyl]-ethylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene,purified lanolin and white petrolatum were added therein. The mixturewas warmed to make it in a liquid state, then stirred until solidifiedto prepare the ointment preparation having the above-mentionedformulation.

What is claimed is: 1.2,3-Dihydro-2,2,4,6-tetramethyl-1-morpholinoacetylamino-7-hydroxy-1H-indene.2.2,3-Dihydro-2,2,4,6-tetramethyl-1-thiomorpholinoacetylamino-7-hydroxy-1H-indene.3. A pharmaceutical composition for improving anoxemic and hypoxicsymptoms and syndromes accompanied therewith comprising apharmaceutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof of claim 1 and a pharmaceutically acceptablecarrier.
 4. A pharmaceutical composition for improving anoxemic andhypoxic symptoms and syndromes accompanied therewith comprising apharmaceutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof of claim 2 and a pharmaceutically acceptablecarrier.